Genetic polymorphisms associated with cardiovascular diseases, methods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with cardiovascular diseases, particularly coronary heart disease (especially myocardial infarction) or hypertension. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application in a continuation application of U.S. non-provisional application Ser. No. 13/964,571, filed on Aug. 12, 2013, which is a continuation application of U.S. non-provisional application Ser. No. 13/486,424, filed on Jun. 1, 2012, which is a divisional application of U.S. non-provisional application Ser. No. 12/500,378, filed on Jul. 9, 2009 (issued as U.S. Pat. No. 8,216,786 on Jul. 10, 2012), which claims priority to U.S. provisional application Ser. No. 61/134,522, filed on Jul. 9, 2008, the contents of each of which are hereby incorporated by reference in their entirety into this application.

FIELD OF THE INVENTION

The present invention is in the field of cardiovascular diseases (CVD), particularly coronary heart disease (CHD), including myocardial infarction (MI), and hypertension. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with CVD. The SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for such uses as identifying an individual who has an increased or decreased risk of developing CVD (particularly CHD, such as MI, and hypertension), for early detection of the disease, for providing clinically important information for the prevention and/or treatment of CVD, for predicting progression or recurrence of CVD, for predicting the seriousness or consequences of CVD in an individual, for determining the prognosis of an individual's recovery from CVD, for screening and selecting therapeutic agents, and for predicting a patient's response to therapeutic agents such as evaluating the likelihood of an individual responding positively to a therapeutic agent such as a statin, particularly for the treatment or prevention of CVD (such as CHD, particularly MI, and hypertension). The SNPs disclosed herein are also useful for human identification applications. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

Cadiovascular Diseases (CVD)

Cardiovascular diseases (CVD) include, for example, coronary heart disease (CHD) and hypertension. CHD includes, for example, myocardial infarction (MI).

Coronary Heart Disease (CHD), Including Myocardial Infarction (MI)

The present invention relates to SNPs that are associated with the occurrence of coronary heart disease (CHD), particularly myocardial infarction (MI).

CHD is defined in the Framingham Heart Study as encompassing MI, angina pectoris, coronary insufficiency (which is manifested as ischemia, that is, impaired oxygen flow to the heart muscle), and coronary heart disease death (Wilson et al., Circulation 97:1837-1847 (1998)). CHD may be recorded through clinical records that indicate the following interventions: coronary artery bypass graft (CABG), angioplasty (e.g., percutaneous transluminal coronary angioplasty (PTCA)), and revascularization (stent placement), in addition to clinical records of MI, angina, or coronary death.

As used herein, CHD is defined in accordance with how this term is defined in the Framingham Heart Study (i.e., as encompassing MI, angina pectoris, coronary insufficiency, and coronary heart disease death). Angina pectoris includes unstable angina in particular.

The SNPs described herein may further be useful for such cardiovascular events as vulnerable plaque and stroke.

Myocardial Infarction (MI)

Myocardial infarction (MI), also referred to as a “heart attack”, is the most common cause of mortality in developed countries. The incidence of MI is still high despite currently available preventive measures and therapeutic intervention. More than 1,500,000 people in the U.S. suffer acute MI each year, many without seeking help due to unrecognized MI, and one third of these people die. The lifetime risk of coronary artery disease events at age 40 is 42.4% for men, nearly one in two, and 24.9% for women, or one in four. D. M. Lloyd-Jones, Lancet 353:89-92 (1999).

MI is a multifactorial disease that involves atherogenesis, thrombus formation and propagation. Thrombosis can result in complete or partial occlusion of coronary arteries. The luminal narrowing or blockage of coronary arteries reduces oxygen and nutrient supply to the cardiac muscle (cardiac ischemia), leading to myocardial necrosis and/or stunning. MI, unstable angina, and sudden ischemic death are clinical manifestations of cardiac muscle damage. All three endpoints are part of acute coronary syndrome since the underlying mechanisms of acute complications of atherosclerosis are considered to be the same.

Atherogenesis, the first step of pathogenesis of MI, is a complex interaction between blood elements, mechanical forces, disturbed blood flow, and vessel wall abnormality that results in plaque accumulation. An unstable (vulnerable) plaque was recognized as an underlying cause of arterial thrombotic events and MI. A vulnerable plaque is a plaque, often not stenotic, that has a high likelihood of becoming disrupted or eroded, thus forming a thrombogenic focus. MI due to a vulnerable plaque is a complex phenomenon that includes: plaque vulnerability, blood vulnerability (hypercoagulation, hypothrombolysis), and heart vulnerability (sensitivity of the heart to ischemia or propensity for arrhythmia). Recurrent myocardial infarction (RMI) can generally be viewed as a severe form of MI progression caused by multiple vulnerable plaques that are able to undergo pre-rupture or a pre-erosive state, coupled with extreme blood coagulability.

The current diagnosis of MI is based on the levels of troponin I or T that indicate the cardiac muscle progressive necrosis, impaired electrocardiogram (ECG), and detection of abnormal ventricular wall motion or angiographic data (the presence of acute thrombi). However, due to the asymptomatic nature of 25% of acute MIs (absence of atypical chest pain, low ECG sensitivity), a significant portion of MIs are not diagnosed and therefore not treated appropriately (e.g., prevention of recurrent MIs).

MI risk assessment and prognosis is currently done using classic risk factors or the recently introduced Framingham Risk Index. Both of these assessments put a significant weight on LDL levels to justify preventive treatment. However, it is well established that half of all MIs occur in individuals without overt hyperlipidemia.

Other emerging risk factors of MI are inflammatory biomarkers such as C-reactive protein (CRP), ICAM-1, SAA, TNF α, homocysteine, impaired fasting glucose, new lipid markers (ox LDL, Lp-a, MAD-LDL, etc.) and pro-thrombotic factors (fibrinogen, PAI-1). These markers have significant limitations such as low specificity and low positive predictive value, and the need for multiple reference intervals to be used for different groups of people (e.g., males-females, smokers-non smokers, hormone replacement therapy users, different age groups). These limitations diminish the utility of such markers as independent prognostic markers for MI screening.

Genetics plays an important role in MI risk. Families with a positive family history of MI account for 14% of the general population, 72% of premature MIs, and 48% of all MIs. R. R. Williams, Am J Cardiology 87:129 (2001). In addition, replicated linkage studies have revealed evidence of multiple regions of the genome that are associated with MI and relevant to MI genetic traits, including regions on chromosomes 14, 2, 3 and 7, implying that genetic risk factors influence the onset, manifestation, and progression of MI. U. Broeckel, Nature Genetics 30:210 (2002); S. Harrap, Arterioscler Thromb Vasc Biol 22:874-878 (2002); A. Shearman, Human Molecular Genetics 9:1315-1320 (2000). Recent association studies have identified allelic variants that are associated with acute complications of CHD, including allelic variants of the ApoE, ApoA5, Lpa, APOCIII, and Klotho genes.

Genetic markers such as single nucleotide polymorphisms (SNPs) are preferable to other types of biomarkers. Genetic markers that are prognostic for MI can be genotyped early in life and could predict individual response to various risk factors. The combination of serum protein levels and genetic predisposition revealed by genetic analysis of susceptibility genes can provide an integrated assessment of the interaction between genotypes and environmental factors, resulting in synergistically increased prognostic value of diagnostic tests.

Thus, there is an urgent need for novel genetic markers that are predictive of predisposition to CHD such as MI, particularly for individuals who are unrecognized as having a predisposition to MI. Such genetic markers may enable prognosis of MI in much larger populations compared with the populations that can currently be evaluated by using existing risk factors and biomarkers. The availability of a genetic test may allow, for example, appropriate preventive treatments for acute coronary events to be provided for susceptible individuals (such preventive treatments may include, for example, statin treatments and statin dose escalation, as well as changes to modifiable risk factors), lowering of the thresholds for ECG and angiography testing, and allow adequate monitoring of informative biomarkers. Moreover, the discovery of genetic markers associated with MI will provide novel targets for therapeutic intervention or preventive treatments of MI, and enable the development of new therapeutic agents for treating or preventing MI and other cardiovascular disorders.

Furthermore, novel genetic markers that are predictive of predisposition to MI can be particularly useful for identifying individuals who are at risk for early-onset MI. “Early-onset MI” may be defined as MI in men who are less than 55 years of age and women who are less than 65 years of age. K. O. Akosah et al., “Preventing myocardial infarction in the young adult in the first place: How do the National Cholesterol Education Panel III guidelines perform?” JACC 41(9):1475-1479 (2003). Individuals who experience early-onset MI may not be effectively identified by current cholesterol treatment guidelines, such as those suggested by the National Cholesterol Education Program. In one study, for example, a significant number of individuals who suffered MI at an earlier age (≤50 years) were shown to have LDL cholesterol below 100 mg/dl. K. O. Akosah et al., “Myocardial infarction in young adults with low-density lipoprotein cholesterol levels less than or equal to 100 mg/dl. Clinical profile and 1-year outcomes.” Chest 120:1953-1958 (2001). Because risk for MI can be reduced by lifestyle changes and by treatment of modifiable risk factors, better methods to identify individuals at risk for early-onset MI could be useful for making preventive treatment decisions, especially considering that these patients may not be identified for medical management by conventional treatment guidelines. Genetic markers for risk of early-onset MI could potentially be incorporated into individual risk assessment protocols, as they have the advantage of being easily detected at any age.

Hypertension

Hypertension is a significant, modifiable risk factor for both CHD and stroke; two of the top three causes of mortality in the United States (Kearney et al., Lancet. 2005; 365:217-223; and Centers for Disease Control and Prevention, National Center for Health Statistics, FastStats). The prevalence of hypertension in US adults is estimated to be 29% (Ostchega et al., 2008, National Center for Health Statistics data brief no. 3), and the prevalence is expected to increase in the future (Kearney et al., Lancet. 2005; 365:217-223; and Hajjar et al., JAMA. 2003; 290:199-206). While about 5% of hypertension has known causes (classified as secondary hypertension), the majority of hypertension is due to unknown causes (classified as essential hypertension) (Cowley et al., Nature Reviews Genetics. 2006; 7:829-840). It is estimated that genetic variation contributes to between 30-60% of inter-individual blood pressure variation (Binder, Curr Opin Cardiol. 2007; 22:176-184) but the identity and nature of the contributing genetic loci are largely unknown.

Statin Treatment

HMG-CoA reductase inhibitors (statins) are used for the treatment and prevention of CVD, particularly MI. Reduction of MI and other coronary events and total mortality by treatment with HMG-CoA reductase inhibitors has been demonstrated in a number of randomized, double-blinded, placebo-controlled prospective trials. D. D. Waters, Clin Cardiol 24(8 Suppl):III3-7 (2001); B. K. Singh and J. L. Mehta, Curr Opin Cardiol 17(5):503-11 (2002). These drugs have their primary effect through the inhibition of hepatic cholesterol synthesis, thereby upregulating LDL receptors in the liver. The resultant increase in LDL catabolism results in decreased circulating LDL, a major risk factor for cardiovascular disease.

Statins can be divided into two types according to their physicochemical and pharmacokinetic properties. Statins such as lovastatin, simvastatin, atorvastatin, and cerevastatin are lipophilic in nature and, as such, diffuse across membranes and thus are highly cell permeable. Hydrophilic statins such as pravastatin are more polar, such that they require specific cell surface transporters for cellular uptake. K. Ziegler and W. Stunkel, Biochim Biophys Acta 1139(3):203-9 (1992); M. Yamazaki et al., Am J Physiol 264(1 Pt 1):G36-44 (1993); T. Komai et al., Biochem Pharmacol 43(4):667-70 (1992). The latter statin utilizes a transporter, OATP2, whose tissue distribution is confined to the liver and, therefore, they are relatively hepato-specific inhibitors. B. Hsiang et al., J Biol Chem 274(52):37161-37168 (1999). The former statins, not requiring specific transport mechanisms, are available to all cells and they can directly impact a much broader spectrum of cells and tissues. These differences in properties may influence the spectrum of activities that each statin possesses. Pravastatin, for instance, has a low myopathic potential in animal models and myocyte cultures compared to lipophilic statins. B. A. Masters et al., Toxicol Appl Pharmacol 131(1):163-174 (1995); K. Nakahara et al., Toxicol Appl Pharmacol 152(1):99-106 (1998); J. C. Reijneveld et al., Pediatr Res 39(6):1028-1035 (1996).

Evidence from gene association studies is accumulating to indicate that responses to drugs are, indeed, at least partly under genetic control. As such, pharmacogenetics—the study of variability in drug responses attributed to hereditary factors in different populations—may significantly assist in providing answers toward meeting this challenge. A. D. Roses, Nature 405(6788):857-865 (2000); V. Mooser et al., J Thromb Haemost 1(7):1398-1402 (2003); L. M. Humma and S. G. Terra, Am J Health Syst Pharm 59(13):1241-1252 (2002). Numerous associations have been reported between selected genotypes, as defined by SNPs and other genetic sequence variations, and specific responses to cardiovascular drugs. Polymorphisms in several genes have been suggested to influence responses to statins including CETP (J. A. Kuivenhoven et al., N Engl J Med 338(2):86-93 (1998)), beta-fibrinogen (M. P. de Maat et al., Arterioscler Thromb Vasc Biol 18(2):265-71 (1998)), hepatic lipase (A. Zambon et al., Circulation 103(6):792-798 (2001)), lipoprotein lipase (J. W. Jukema et al., Circulation 94(8):1913-1918 (1996)), glycoprotein IIIa (P. F. Bray et al., Am J Cardiol 88(4):347-352 (2001)), stromelysin-1 (M. P. de Maat et al., Am J Cardiol 83(6):852-856 (1999)), and apolipoprotein E (L. U. Gerdes et al., Circulation 101(12):1366-1371 (2000); J. Pedro-Botet et al., Atherosclerosis 158(1):183-193 (2001)). Some of these variants were shown to effect clinical events while others were associated with changes in surrogate endpoints.

Thus, there is a need for genetic markers that can be used to predict an individual's responsiveness to statins. For example, there is a growing need to better identify people who have the highest chance of benefiting from statins, and those who have the lowest risk of developing side-effects. For example, severe myopathies represent a significant risk for a low percentage of the patient population, and this may be a particular concern for patients who are treated more aggressively with statins.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence gives rise to genetic polymorphisms, including SNPs.

Approximately 90% of all genetic polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, SNP locus, SNP marker, or marker) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an “indel.” Weber et al., “Human diallelic insertion/deletion polymorphisms,” Am J Hum Genet 71(4):854-62 (October 2002).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP,” “polymorphism,” “mutation,” “mutant,” “variation,” and “variant” are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e., a non-synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non-synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra-allelic, the vast majority of the SNPs are bi-allelic, and are thus often referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases. Stephens et al., Science 293:489-493 (July 2001).

Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i.e., non-synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g., genetic disease. Examples of genes in which a SNP within a coding sequence causes a genetic disease include sickle cell anemia and cystic fibrosis.

Causative SNPs do not necessarily have to occur in coding regions; causative SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disease-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disease. These SNPs, although not causative, are nonetheless also useful for diagnostics, disease predisposition screening, and other uses.

An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as CVD, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as “healthy” or “normal” individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well-characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific pathological condition, such as pathologies related to CVD and in particular, CHD (particularly MI) and hypertension. Once a statistically significant association is established between one or more SNP(s) and a pathological condition (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene, regulatory region, etc.) that influences the pathological condition or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed “pharmacogenomics”). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. Linder et al., Clinical Chemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al., Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

The present invention relates to the identification of SNPs, as well as unique combinations of such SNPs and haplotypes of SNPs, that are associated with cardiovascular diseases (CVD), particularly coronary heart disease (CHD), especially myocardial infarction (MI), and hypertension. The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the diagnosis, prognosis, treatment, and/or prevention of CVD (particularly CHD, such as MI, and hypertension).

Based on the identification of SNPs associated with CVD (particularly CHD, especially MI, and hypertension), the present invention also provides methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides, for example, SNPs associated with CVD, isolated nucleic acid molecules (including DNA and RNA molecules) containing these SNPs, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals who have an altered (i.e., increased or decreased) risk of developing CVD (particularly CHD, such as MI, and hypertension), methods for determining the risk of an individual for recurring CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), methods for prognosing the severity or consequences of CVD, methods of treating an individual who has an increased risk for CVD, and methods for identifying individuals (e.g., determining a particular individual's likelihood) who have an altered (i.e., increased or decreased) likelihood of responding to a drug treatment, particularly drug treatment of CVD (e.g., treatment or prevention of CHD, such as MI, or hypertension), based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNP sites disclosed herein or the detection of one or more encoded variant products (e.g., variant mRNA transcripts or variant proteins), methods of identifying individuals who are more or less likely to respond to a treatment such as statin treatment (or more or less likely to experience undesirable side effects from a treatment), methods of screening for compounds useful in the treatment or prevention of a disorder associated with a variant gene/protein, compounds identified by these methods, methods of treating or preventing disorders mediated by a variant gene/protein, methods of using the novel SNPs of the present invention for human identification, etc.

The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer a treatment such as a statin to an individual having CVD, or who is at risk for developing CVD in the future, or who has previously had CVD, methods for selecting a particular treatment regimen such as dosage and frequency of administration of a therapeutic agent such as a statin, or a particular form/type of a therapeutic agent such as a particular pharmaceutical formulation or compound, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, etc. The present invention also provides methods for selecting individuals to whom a therapeutic agent (e.g., a statin) will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a therapeutic agent (e.g., a statin) based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively to the therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to the therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular therapeutic agent such as a statin based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them). The present invention further provides methods for reducing an individual's risk of developing CVD (such as CHD, particularly MI, and hypertension) using a drug treatment (e.g., statin treatment), including preventing recurring CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), when said individual carries one or more SNPs identified herein as being associated with CVD and/or response to statin treatment.

In Tables 1 and 2, the present invention provides gene information, references to the identification of transcript sequences (SEQ ID NOS:1-307), encoded amino acid sequences (SEQ ID NOS:308-614), genomic sequences (SEQ ID NOS:1015-1400), transcript-based context sequences (SEQ ID NOS:615-1014) and genomic-based context sequences (SEQ ID NOS:1401-4006 and 5414) that contain the SNPs of the present invention, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The actual transcript sequences (SEQ ID NOS:1-307), amino acid sequences (SEQ ID NOS:308-614), genomic sequences (SEQ ID NOS:1015-1400), transcript-based SNP context sequences (SEQ ID NOS:615-1014), and genomic-based SNP context sequences (SEQ ID NOS:1401-4006 and 5414), together with primer sequences (SEQ ID NOS:4007-5413 and 5415-5416) are provided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered risk for developing CVD, such as CHD (particularly MI) or hypertension (including, for example, a first incidence and/or a recurrence of the disease), in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-307, SEQ ID NOS:615-1014, SEQ ID NOS:1015-1400, and SEQ ID NOS:1401-4006 and 5414 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and/or Table 2, and the presence of the SNP is indicative of an altered risk for CVD in said individual. In certain embodiments, the CVD is CHD (particularly MI) or hypertension. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided as isolated nucleic acid molecules. These SNPs are associated with CVD (particular CHD, especially MI, and hypertension) such that they can have a variety of uses in the diagnosis, prognosis, treatment, and/or prevention of CVD and related pathologies. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) is provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment.

Various embodiments of the invention also provide kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing detection reagents. In a specific embodiment, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing CVD (e.g., CHD, particularly MI, or hypertension) by detecting the presence or absence of one or more SNP alleles disclosed herein. In another embodiment, a method for diagnosis of CVD by detecting the presence or absence of one or more SNP alleles disclosed herein is provided. The present invention also provides methods for evaluating whether an individual is likely (or unlikely) to respond to a treatment (e.g., a therapeutic agent such as a statin) by detecting the presence or absence of one or more SNP alleles disclosed herein.

The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents or pharmaceutical compounds useful in the treatment or prevention of CVD (particularly CHD, such as MI, or hypertension).

An aspect of this invention is a method for treating or preventing CVD, such as CHD (particularly MI) or hypertension (including, for example, a first occurrence and/or a recurrence of the disease), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agent(s) counteracting the effects of the disease, such as by inhibiting (or stimulating) the activity of a gene, transcript, and/or encoded protein identified in Tables 1 and 2. In certain exemplary embodiments, the agent(s) comprise a statin.

Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating CVD (particularly CHD, such as MI, or hypertension), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.

Another aspect of this invention is a method for treating or preventing CVD (such as CHD, particularly MI, or hypertension), in a human subject, in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents (e.g., one or more statins) counteracting the effects of the disease.

Another aspect of the invention is a method for identifying a human who is likely to benefit from a treatment (e.g., a therapeutic agent, particularly a statin), in which the method comprises detecting an allele of one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele indicates that said human is likely to benefit from the treatment.

Another aspect of the invention is a method for identifying a human who is likely to benefit from a treatment (e.g., a therapeutic agent, particularly a statin), in which the method comprises detecting an allele of one or more SNPs that are in LD with one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele of the LD SNP indicates that said human is likely to benefit from the treatment.

Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the preferred embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.

Description of the Text (ASCII) File Submitted Electronically Via EFS-Web

The following text (ASCII) files are submitted electronically via EFS-Web as part of the instant application:

1) File SEQLIST_CD26ORD.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:1-307) and protein sequences (SEQ ID NOS:308-614) as referred to in Table 1, and genomic sequences (SEQ ID NOS:1015-1400) as referred to in Table 2, for each CVD-associated gene (or genomic region for intergenic SNPs) that contains one or more SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as referred to in Table 1 (SEQ ID NOS:615-1014) and genomic-based context sequences as referred to in Table 2 (SEQ ID NOS:1401-4006 and 5414). In addition, the Sequence Listing provides the primer sequences from Table 5 (SEQ ID NOS:4007-5413 and 5415-5416). The context sequences generally provide 100 bp upstream (5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middle of the context sequence, for a total of 200 bp of context sequence surrounding each SNP. File SEQLIST_CD26ORD.txt is 52,636 KB in size, and was created on Jul. 8, 2009.

2) File TABLE1_CD26ORD.txt provides Table 1, which is 477 KB in size, and was created on Jul. 7, 2009.

3) File TABLE2_CD26ORD.txt provides Table 2, which is 1,961 KB in size, and was created on Jul. 8, 2009.

4) File TABLE3_CD26ORD.txt provides Table 3, which is 1 KB in size, and was created on Jul. 6, 2009.

5) File TABLE4_CD26ORD.txt provides Table 4, which is 1 KB in size, and was created on Jul. 6, 2009.

These text files are hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).

LENGTHY TABLES The patent contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US10584384B2). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Description of Table 1 and Table 2

Table 1 and Table 2 (both submitted electronically via EFS-Web) disclose the SNP and associated gene/transcript/protein information of the present invention. For each gene, Table 1 provides a header containing gene, transcript and protein information, followed by a transcript and protein sequence identifier (SEQ ID NO), and then SNP information regarding each SNP found in that gene/transcript including the transcript context sequence. For each gene in Table 2, a header is provided that contains gene and genomic information, followed by a genomic sequence identifier (SEQ ID NO) and then SNP information regarding each SNP found in that gene, including the genomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences. In some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions. Additionally, in either Table 1 or 2 a “Related Interrogated SNP” may be listed following a SNP which is determined to be in LD with that interrogated SNP according to the given Power value. SNPs can be readily cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers and/or public rs identification numbers, and to the Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in         the Table),     -   a gene symbol, along with an Entrez gene identification number         (Entrez Gene database, National Center for Biotechnology         Information (NCBI), National Library of Medicine, National         Institutes of Health)     -   a gene name,     -   an accession number for the transcript (e.g., RefSeq NM number,         or a Celera hCT identification number if no RefSeq NM number is         available) (Table 1 only),     -   an accession number for the protein (e.g., RefSeq NP number, or         a Celera hCP identification number if no RefSeq NP number is         available) (Table 1 only),     -   the chromosome number of the chromosome on which the gene is         located,     -   an OMIM (“Online Mendelian Inheritance in Man” database, Johns         Hopkins University/NCBI) public reference number for the gene,         and OMIM information such as alternative gene/protein name(s)         and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multiple transcript/protein entries may be provided for a single gene entry in Table 1; i.e., for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.

Following the gene/transcript/protein information is a transcript context sequence (Table 1), or a genomic context sequence (Table 2), for each SNP within that gene.

After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as “Intergenic region:” followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (such SNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP context sequences are all provided in the Sequence Listing. The transcript-based SNP context sequences are provided in both Table 1 and also in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in the Sequence Listing. The genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOs are indicated in Table 1 for the transcript-based context sequences (SEQ ID NOS:615-1014); SEQ ID NOs are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS:1401-4006 and 5414).

The SNP information includes:

-   -   Context sequence (taken from the transcript sequence in Table 1,         the genomic sequence in Table 2) with the SNP represented by its         IUB code, including 100 bp upstream (5′) of the SNP position         plus 100 bp downstream (3′) of the SNP position (the         transcript-based SNP context sequences in Table 1 are provided         in the Sequence Listing as SEQ ID NOS:615-1014; the         genomic-based SNP context sequences in Table 2 are provided in         the Sequence Listing as SEQ ID NOS:1401-4006 and 5414).     -   Celera hCV internal identification number for the SNP (in some         instances, an “hDV” number is given instead of an “hCV” number;         “hDV68873046” may be interchangeably referred to herein as         “hCV29714327”).     -   The corresponding public identification number for the SNP, the         rs number.     -   “SNP Chromosome Position” indicates the nucleotide position of         the SNP along the entire sequence of the chromosome as provided         in NCBI Genome Build 36.     -   SNP position (nucleotide position of the SNP within the given         transcript sequence (Table 1) or within the given genomic         sequence (Table 2)).     -   “Related Interrogated SNP” is the interrogated SNP with which         the listed SNP is in LD at the given value of Power.     -   SNP source (may include any combination of one or more of the         following five codes, depending on which internal sequencing         projects and/or public databases the SNP has been observed in:         “Applera”=SNP observed during the re-sequencing of genes and         regulatory regions of 39 individuals, “Celera”=SNP observed         during shotgun sequencing and assembly of the Celera human         genome sequence, “Celera Diagnostics”=SNP observed during         re-sequencing of nucleic acid samples from individuals who have         a disease, “dbSNP”=SNP observed in the dbSNP public database,         “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP         observed in the Human Gene Mutation Database (HGMD) public         database, “HapMap”=SNP observed in the International HapMap         Project public database, “CSNP”=SNP observed in an internal         Applied Biosystems (Foster City, Calif.) database of coding SNPS         (cSNPs).

Note that multiple “Applera” source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re-sequencing results (e.g., observed allele counts) from each of these amplification products is being provided.

-   -   Population/allele/allele count information in the format of         [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count)         total (first_allele,total count|second_allele,total count)]. The         information in this field includes populations/ethnic groups in         which particular SNP alleles have been observed         (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and         “afr”=African-American, “jpn”=Japanese, “ind”=Indian,         “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,         “no_pop”=no population information available), identified SNP         alleles, and observed allele counts (within each population         group and total allele counts), where available [“-” in the         allele field represents a deletion allele of an         insertion/deletion (“indel”) polymorphism (in which case the         corresponding insertion allele, which may be comprised of one or         more nucleotides, is indicated in the allele field on the         opposite side of the “|”); “-” in the count field indicates that         allele count information is not available]. For certain SNPs         from the public dbSNP database, population/ethnic information is         indicated as follows (this population information is publicly         available in dbSNP): “HISP1”=human individual DNA (anonymized         samples) from 23 individuals of self-described HISPANIC         heritage; “PAC1”=human individual DNA (anonymized samples) from         24 individuals of self-described PACIFIC RIM heritage;         “CAUC1”=human individual DNA (anonymized samples) from 31         individuals of self-described CAUCASIAN heritage; “AFR1”=human         individual DNA (anonymized samples) from 24 individuals of         self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human         individual DNA (anonymized samples) from 102 individuals of         self-described heritage; “PA130299515”; “SC_12_A”=SANGER 12 DNAs         of Asian origin from Corielle cell repositories, 6 of which are         male and 6 female; “SC_12_C”=SANGER 12 DNAs of Caucasian origin         from Corielle cell repositories from the CEPH/UTAH library, six         male and six female; “SC_12_AA”=SANGER 12 DNAs of         African-American origin from Corielle cell repositories 6 of         which are male and 6 female; “SC_95_C”=SANGER 95 DNAs of         Caucasian origin from Corielle cell repositories from the         CEPH/UTAH library; and “SC_12_CA”=Caucasians—12 DNAs from         Corielle cell repositories that are from the CEPH/UTAH library,         six male and six female.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African-American (“afr”) allele counts is up to 38, the sum of the Caucasian allele counts (“cau”) is up to 40, and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count information corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the corresponding listing of population/allele/count information.

-   -   SNP type (e.g., location within gene/transcript and/or predicted         functional effect) [“MISSENSE MUTATION”=SNP causes a change in         the encoded amino acid (i.e., a non-synonymous coding SNP);         “SILENT MUTATION”=SNP does not cause a change in the encoded         amino acid (i.e., a synonymous coding SNP); “STOP CODON         MUTATION”=SNP is located in a stop codon; “NONSENSE         MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is         located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a         3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a         putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative         3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice         site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located         in an acceptor splice site (3′ intron boundary); “CODING         REGION”=SNP is located in a protein-coding region of the         transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is         located in an intron; “hmCS”=SNP is located in a human-mouse         conserved segment; “TFBS”=SNP is located in a transcription         factor binding site; “UNKNOWN”=SNP type is not defined;         “INTERGENIC”=SNP is intergenic, i.e., outside of any gene         boundary].     -   Protein coding information (Table 1 only), where relevant, in         the format of [protein SEQ ID NO, amino acid position, (amino         acid-1, codon1) (amino acid-2, codon2)]. The information in this         field includes SEQ ID NO of the encoded protein sequence,         position of the amino acid residue within the protein identified         by the SEQ ID NO that is encoded by the codon containing the         SNP, amino acids (represented by one-letter amino acid codes)         that are encoded by the alternative SNP alleles (in the case of         stop codons, “X” is used for the one-letter amino acid code),         and alternative codons containing the alternative SNP         nucleotides which encode the amino acid residues (thus, for         example, for missense mutation-type SNPs, at least two different         amino acids and at least two different codons are generally         indicated; for silent mutation-type SNPs, one amino acid and at         least two different codons are generally indicated, etc.). In         instances where the SNP is located outside of a protein-coding         region (e.g., in a UTR region), “None” is indicated following         the protein SEQ ID NO.

Note that SNPs can be cross-referenced between any of Tables 1-22 herein based on their hCV and/or rs identification numbers. However, two of the SNPs that are included in the tables may possess two different hCV identification numbers, as follows:

-   -   SNP hCV25473098 is the same as SNP hCV16173091 set forth in         Tables 1-2.     -   SNP hCV16192174 is the same as SNP hCV22271999 set forth in         Tables 1-2.     -   SNP hCV25640504 can be represented by either genomic context         sequences SEQ ID NOS:2554 or 5414 (each of which is set forth in         Table 2 and the Sequence Listing), and can be assayed using         either allele-specific primers SEQ ID NOS:4580-4581 or SEQ ID         NOS:5415-5416 (any of which can be used in combination with         common primer SEQ ID NO:4582) (each of which allele-specific and         common primers is set forth in Table 5 and the Sequence         Listing).

Description of Table 3 and Table 4

Tables 3 and 4 (both submitted electronically via EFS-Web) provide a list of a subset of SNPs from Table 1 (in the case of Table 3) or Table 2 (in the case of Table 4) for which the SNP source falls into one of the following three categories: 1) SNPs for which the SNP source is only “Applera” and none other, 2) SNPs for which the SNP source is only “Celera Diagnostics” and none other, and 3) SNPs for which the SNP source is both “Applera” and “Celera Diagnostics” but none other.

These SNPs have not been observed in any of the public databases (dbSNP, HGBASE, and HGMD), and were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., “Celera” SNP source). Tables 3 and 4 provide the hCV identification number (or hDV identification number for SNPs having “Celera Diagnostics” SNP source) and the SEQ ID NO of the context sequence for each of these SNPs.

Description of Table 5

Table 5 provides sequences (SEQ ID NOS:4007-5413 and 5415-5416) of primers that may be used to assay the SNPs disclosed herein by allele-specific PCR or other methods, such as for uses related to CVD.

Table 5 provides the following:

-   -   the column labeled “Marker” provides an hCV identification         number for each SNP that can be detected using the corresponding         primers.     -   the column labeled “Alleles” designates the two alternative         alleles (i.e., nucleotides) at the SNP site. These alleles are         targeted by the allele-specific primers (the allele-specific         primers are shown as Primer 1 and Primer 2). Note that alleles         may be presented in Table 5 based on a different orientation         (i.e., the reverse complement) relative to how the same alleles         are presented in Tables 1-2.     -   the column labeled “Primer 1 (Allele-Specific Primer)” provides         an allele-specific primer that is specific for an allele         designated in the “Alleles” column.     -   the column labeled “Primer 2 (Allele-Specific Primer)” provides         an allele-specific primer that is specific for the other allele         designated in the “Alleles” column.     -   the column labeled “Common Primer” provides a common primer that         is used in conjunction with each of the allele-specific primers         (i.e., Primer 1 and Primer 2) and which hybridizes at a site         away from the SNP position.

All primer sequences are given in the 5′ to 3′ direction.

Each of the nucleotides designated in the “Alleles” column matches or is the reverse complement of (depending on the orientation of the primer relative to the designated allele) the 3′ nucleotide of the allele-specific primer (i.e., either Primer 1 or Primer 2) that is specific for that allele.

Description of Table 6

Table 6 provides a list of LD SNPs that are related to and derived from certain interrogated SNPs. The interrogated SNPs, which are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 6, are statistically significantly associated with CVD, as described and shown herein, particularly in Tables 7-22 and in the Examples section below. The LD SNPs are provided as an example of SNPs which can also serve as markers for disease association based on their being in LD with an interrogated SNP. The criteria and process of selecting such LD SNPs, including the calculation of the r² value and the r² threshold value, are described in Example 6, below.

In Table 6, the column labeled “Interrogated SNP” presents each marker as identified by its unique hCV identification number. The column labeled “Interrogated rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “LD SNP” presents the hCV numbers of the LD SNPs that are derived from their corresponding interrogated SNPs. The column labeled “LD SNP rs” presents the publicly known rs identification number for the corresponding hCV number. The column labeled “Power” presents the level of power where the r² threshold is set. For example, when power is set at 0.51, the threshold r² value calculated therefrom is the minimum r² that an LD SNP must have in reference to an interrogated SNP, in order for the LD SNP to be classified as a marker capable of being associated with a disease phenotype at greater than 51% probability. The column labeled “Threshold r²” presents the minimum value of r² that an LD SNP must meet in reference to an interrogated SNP in order to qualify as an LD SNP. The column labeled “r²” presents the actual r² value of the LD SNP in reference to the interrogated SNP to which it is related.

Description of Tables 7-22

Tables 7-22 provide the results of statistical analyses for SNPs disclosed in Tables 1 and 2 (SNPs can be cross-referenced between all the tables herein based on their hCV and/or rs identification numbers). The results shown in Tables 7-22 provide support for the association of these SNPs with CVD, particularly CHD (especially MI) and/or hypertension.

Table 7 provides association test results from two MI case-control studies (see Example 1 below).

Table 8 provides descriptive information by race and GOSR2 genotype (see Example 1 below).

Table 9 provides OR and 95% CI for the association between GOSR2 (Lys67Arg, rs197922), hypertension, and carotid artery thickness (see Example 1 below).

Table 10 provides SNPs surrounding GOSR2 SNP rs197922 (hCV2275273) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).

Table 11 provides risk factors for MI in participants of three case-control studies (see Example 2 below).

Table 12 provides twenty-four SNPs associated with MI in Study 1 (UCSF) and Study 2 (UCSF) (see Example 2 below).

Table 13 provides results for genotypic association of five SNPs in Study 3 (CCF) (see Example 2 below).

Table 14 provides SNPs surrounding the ENO1 SNP rs1325920 (hCV8824241) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).

Table 15 provides SNPs surrounding the FXN SNP rs10890 (hCV1463226) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).

Table 16 provides SNPs surrounding the RERE SNP rs10779705 (hCV32055477) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).

Table 17 provides SNPs surrounding VAMP8 rs1010 (hCV2091644) that are associated with CVD, particularly CHD, and especially MI (see Example 3 below).

Tables 18 and 19 provide SNPs surrounding the LPA SNP rs3798220 (hCV25930271) that are associated with CVD, particularly CHD, and especially MI. Table 18 provides results of an analysis of the UCSF1 sample set, and Table 19 provides results of a meta-analysis of the UCSF1 and UCSF2 sample sets combined. The SNPs provided in Table 19 are also associated with Lp(a) levels (see Example 3 below).

Table 20 provides SNPs (from a functional genome scan (FGS)) associated with CVD, particularly CHD, and especially MI, in two studies (see Example 4 below).

Table 21 provides SNPs associated with reduction of CHD risk, particularly risk for MI and recurrent MI, by Pravastatin in the CARE study, and Table 22 provides SNPs associated with risk of CHD, particularly risk for MI and recurrent MI, in the placebo arm of the CARE study. The SNPs provided in Table 22 are a subset of the SNPs provided in Table 21; thus, the SNPs provided in Table 22 are associated with both increased CHD risk as well as reduction of CHD risk by statin treatment (e.g., Pravastatin) (see Example 5 below).

Table 21 provides SNPs for which the effect of pravastatin on the primary endpoint of the CARE study (identified as “endpt1” in the Endpoint column) or the recurrent MI endpoint (identified as “rmi” in the Endpoint column) was analyzed by genotype subgroups and for which pravastatin reduced risk in one genotype subgroup but not in another (P-interaction between statin treatment and genotype for the enpdpoint <0.1).

Table 22 provides a subset of SNPs from Table 21 that were associated (p<0.1) with time to occurrence of first event, either the CARE primary endpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebo group of the CARE study. In Table 22, the HR (including lower and upper confidence intervals) and p-values indicated for each SNP correspond to Allele 1 (Allele 2 is the reference allele, which is considered to have HR=1).

In Tables 21-22, the column labeled “Endpoint” indicates whether the endpoint that was analyzed was the primary endpoint of the CARE study (a composite endpoint of fatal coronary event or nonfatal MI, and identified as “endpt1”) or a composite endpoint of confirmed fatal or nonfatal MI (identified as “rmi”). Also in Tables 21-22, the column labeled “Events” indicates the number of individuals in the CARE study who had an event (a fatal coronary event or nonfatal MI if “endpt1” is indicated in the Endpoint column, or a fatal or nonfatal MI if “rmi” is indicated in the Endpoint column). Table 22 indicates, for each SNP, the number of individuals in the placebo arm of the CARE study who had an event (column labeled “Events (placebo arm)”) and the total number of individuals (column labeled “Total Patients (placebo arm)”). Table 21 indicates, for each SNP, the number of individuals who had an event in each of the Pravastatin and placebo arms of the CARE study (columns labeled “Events (Pravastatin arm)” and “Events (placebo arm)”, respectively) and the number of individuals who did not have an event in each of the Pravastatin and placebo arms of the CARE study (columns labeled “Nonevent (Pravastatin arm)” and “Nonevent (placebo arm)”, respectively).

Throughout Tables 7-22, with respect to model, “add” is additive, “rec” is recessive, “dom” is dominant, “het” is heterozygotes compared with reference homozygotes, and “hom” is non-reference homozygotes compared with reference homozygotes, and with respect to strata, “M” is males only and “F” is females only.

Throughout Tables 7-22, “OR” refers to the odds ratio, “HR” refers to the hazard ratio, and “90% CI” or “95% CI” refers to the 90% or 95% confidence interval (respectively) for the odds ratio or hazard ratio (“OR95U” and “OR95L” refer to the upper and lower 95% confidence intervals, respectively, for the odds ratio; and “HR95U” and “HR95L” refer to the upper and lower 95% confidence intervals, respectively, for the hazard ratio). Odds ratios (OR) or hazard ratios (HR) that are greater than one indicate that a given allele is a risk allele (which may also be referred to as a susceptibility allele), whereas odds ratios that are less than one indicate that a given allele is a non-risk allele (which may also be referred to as a protective allele). For a given risk allele, the other alternative allele at the SNP position (which can be derived from the information provided in Tables 1-2, for example) may be considered a non-risk allele. For a given non-risk allele, the other alternative allele at the SNP position may be considered a risk allele.

Thus, with respect to disease risk (e.g., CVD such as CHD, particularly MI, or hypertension), if the risk estimate (odds ratio or hazard ratio) for a particular allele at a SNP position is greater than one, this indicates that an individual with this particular allele has a higher risk for the disease than an individual who has the other allele at the SNP position. In contrast, if the risk estimate (odds ratio or hazard ratio) for a particular allele is less than one, this indicates that an individual with this particular allele has a reduced risk for the disease compared with an individual who has the other allele at the SNP position.

With respect to drug response (e.g., response to a statin), if the risk estimate (odds ratio or hazard ratio) of those treated with the drug (e.g., a statin) compared with those treated with a placebo within a particular genotype is less than one, this indicates that an individual with this particular genotype would benefit from the drug (an odds ratio or hazard ratio equal to one would indicate that the drug has no effect). As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment) is defined as achieving a reduced risk for a disease that the drug is intended to treat or prevent (e.g., CVD such as CHD, particularly MI, or hypertension) by administering the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with cardiovascular diseases (CVD), particularly coronary heart disease (CHD), especially myocardial infarction (MI), and hypertension. The present invention further provides nucleic acid molecules containing these SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The SNPs disclosed herein are useful for diagnosing, prognosing, screening for, and evaluating predisposition to CVD and related pathologies in humans. The SNPs disclosed herein may also be used for predicting, screening for, and evaluating response to a treatment (e.g., a therapeutic agent, particularly a statin), particularly treatment or prevention of CVD, in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic and preventive agents.

A large number of SNPs have been identified from re-sequencing DNA from 39 individuals, and they are indicated as “Applera” SNP source in Tables 1-2. Their allele frequencies observed in each of the Caucasian and African-American ethnic groups are provided. Additional SNPs included herein were previously identified during “shotgun” sequencing and assembly of the human genome, and they are indicated as “Celera” SNP source in Tables 1 and 2. Furthermore, the information provided in Tables 1 and 2, particularly the allele frequency information obtained from 39 individuals and the identification of the precise position of each SNP within each gene/transcript, allows haplotypes (i.e., groups of SNPs that are co-inherited) to be readily inferred. The present invention encompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated with CVD (particularly CHD, especially MI, and hypertension), as well as combinations of SNPs and haplotypes, polymorphic/variant transcript sequences (SEQ ID NOS:1-307) and genomic sequences (SEQ ID NOS:1015-1400) containing SNPs, encoded amino acid sequences (SEQ ID NOS:308-614), and both transcript-based SNP context sequences (SEQ ID NOS:615-1014) and genomic-based SNP context sequences (SEQ ID NOS:1401-4006 and 5414) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing CVD, methods of determining if an individual is likely to respond to a particular treatment such as a therapeutic agent such as a statin (particularly for treating or preventing CVD), methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as CVD, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment/preventive strategy or therapeutic agent, methods of treating or preventing a disorder associated with a variant gene/protein, and methods of using the SNPs of the present invention for human identification.

The present invention further provides methods for selecting or formulating a treatment regimen (e.g., methods for determining whether or not to administer a therapeutic agent, particularly a statin, to an individual having CVD, or who is at risk for developing CVD in the future, or who has previously had CVD, methods for selecting a particular treatment regimen such as dosage and frequency of administration of a therapeutic agent (e.g., a statin), or a particular form/type of a therapeutic agent such as a particular pharmaceutical formulation or compound, methods for administering an alternative treatment to individuals who are predicted to be unlikely to respond positively to a particular treatment, etc.), and methods for determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, etc. The present invention also provides methods for selecting individuals to whom a therapeutic agent (e.g., a statin) will be administered based on the individual's genotype, and methods for selecting individuals for a clinical trial of a therapeutic agent (e.g., a statin) based on the genotypes of the individuals (e.g., selecting individuals to participate in the trial who are most likely to respond positively to a therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to a therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular agent such as a statin based on their SNP genotype(s) to participate in a clinical trial of another therapeutic agent that may benefit them).

The present invention may include novel SNPs associated with CVD and/or statin response, as well as SNPs that were previously known in the art, but were not previously known to be associated with CVD and/or statin response. Accordingly, the present invention may provide novel compositions and methods based on novel SNPs disclosed herein, and may also provide novel methods of using known, but previously unassociated, SNPs in methods relating to, for example, evaluating an individual's likelihood of having or developing CVD (particularly CHD, such as MI, and hypertension), predicting the likelihood of an individual experiencing a reoccurrence of CVD (e.g., experiencing recurrent CHD, particularly recurrent MI, or recurrent hypertension), prognosing the severity of CVD in an individual, or prognosing an individual's recovery from CVD, and methods relating to evaluating an individual's likelihood of responding to a treatment such as a particular therapeutic agent, especially a statin (particularly for treatment, including preventive treatment, of CVD). In Tables 1 and 2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: “dbSNP”=SNP observed in dbSNP, “HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the Human Gene Mutation Database (HGMD).

Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) or increased likelihood of responding to a treatment such as a statin (particularly treatment, including preventive treatment, of CVD), or a decreased risk of having or developing CVD or decreased likelihood of responding to a treatment. Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) or increased likelihood of responding to a treatment, other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing CVD or decreased likelihood of responding to a treatment. Similarly, particular SNP alleles of the present invention can be associated with either an increased or decreased likelihood of having a recurrence of CVD (e.g., recurrent CHD, particularly recurrent MI, or recurrent hypertension), of fully recovering from CVD, of experiencing toxic effects from a particular treatment or therapeutic compound, etc. The term “altered” may be used herein to encompass either of these two possibilities (e.g., an increased or a decreased risk/likelihood). SNP alleles that are associated with a decreased risk of having or developing CVD (e.g., CHD, such as MI, or hypertension) may be referred to as “protective” alleles, and SNP alleles that are associated with an increased risk of having or developing CVD may be referred to as “susceptibility” alleles, “risk” alleles, or “risk factors”.

Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the “wild-type,” “reference,” or “normal” protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e., a missense mutation) disclosed by the present invention. Variant peptides/polypeptides/proteins of the present invention can also result from a nonsense mutation (i.e., a SNP that creates a premature stop codon, a SNP that generates a read-through mutation by abolishing a stop codon), or due to any SNP disclosed by the present invention that otherwise alters the structure, function, activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position (wherein at least two alternative nucleotides are present in the population at the SNP position, in accordance with the inherent definition of a SNP) or may refer to an amino acid residue that is encoded by the codon which contains the SNP position (where the alternative nucleotides that are present in the population at the SNP position form alternative codons that encode different amino acid residues). An “allele” may also be referred to herein as a “variant”. Also, an amino acid residue that is encoded by a codon containing a particular SNP may simply be referred to as being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”, or “as designated by” may be used herein to refer to a SNP within a sequence (e.g., a polynucleotide context sequence surrounding a SNP), such as in the context of “a polymorphism as represented by position 101 of SEQ ID NO:X or its complement”. Typically, the sequence surrounding a SNP may be recited when referring to a SNP, however the sequence is not intended as a structural limitation beyond the specific SNP position itself. Rather, the context sequence is recited merely as a way of referring to the SNP (in this example, “SEQ ID NO:X or its complement” is recited in order to refer to the SNP located at position 101 of SEQ ID NO:X, but SEQ ID NO:X or its complement is not intended as a structural limitation beyond the specific SNP position itself). In other words, it is recognized that the context sequence of SEQ ID NO:X in this example may contain one or more polymorphic nucleotide positions outside of position 101 and therefore an exact match over the full-length of SEQ ID NO:X is irrelevant since SEQ ID NO:X is only meant to provide context for referring to the SNP at position 101 of SEQ ID NO:X Likewise, the length of the context sequence is also irrelevant (100 nucleotides on each side of a SNP position has been arbitrarily used in the present application as the length for context sequences merely for convenience and because 201 nucleotides of total length is expected to provide sufficient uniqueness to unambiguously identify a given nucleotide sequence). Thus, since a SNP is a variation at a single nucleotide position, it is customary to refer to context sequence (e.g., SEQ ID NO:X in this example) surrounding a particular SNP position in order to uniquely identify and refer to the SNP. Alternatively, a SNP can be referred to by a unique identification number such as a public “rs” identification number or an internal “hCV” identification number, such as provided herein for each SNP (e.g., in Tables 1-2).

As used herein, the term “benefit” (with respect to a preventive or therapeutic drug treatment such as a statin) is defined as achieving a reduced risk for a disease that the drug (e.g., statin) is intended to treat or prevent (e.g., CVD such as CHD, particularly MI, and hypertension) by administrating the drug treatment, compared with the risk for the disease in the absence of receiving the drug treatment (or receiving a placebo in lieu of the drug treatment) for the same genotype. The term “benefit” may be used herein interchangeably with terms such as “respond positively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are used interchangeably, and may include, but are not limited to, small molecule compounds, biologics (e.g., antibodies, proteins, protein fragments, fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc., which may be used for therapeutic and/or preventive treatment of a disease (e.g., CVD such as CHD, particularly MI, or hypertension).

As used herein, a “drug”, “therapeutic agent”, or “treatment”, may include any agent used in the treatment (including therapeutic or preventive treatment) of CVD, particularly CHD (e.g., MI) or hypertension, such as, for example, a statin such as pravastatin (Pravachol®), atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®), rosuvastatin (Crestor®), simvastatin (Zocor®), and storvastatin, as well as combination therapies that include a statin such as simvastatin+ezetimibe (Vytorin®), lovastatin+niacin extended-release (Advicor®), and atorvastatin+amlodipine besylate (Caduet®).

Hormone Replacement Therapy (HRT)

Certain aspects of the invention relate to methods of using SNP rs3798220 (which is also referred to herein as hCV25930271) for utilities related to hormone replacement therapy (HRT), particularly methods that relate to carriers of the rs3798220 risk allele (C) benefiting from hormone replacement therapy.

SNP rs3798220, which is in the LPA gene, is associated with risk of CVD, particularly MI (as described herein, particularly in Example 2 below; also see Luke et al. ATVB 2007; 27:2030-2036, which is incorporated herein by reference in its entirety). SNP rs3798220 is also associated with Lp(a) levels. Shilpak et al. (JAMA. 2000; 283:1845) have shown in the HERS study that women in the hormone replacement therapy (estrogen+progestin treatment) group with high baseline Lp(a) have significant reduction of cardiovascular events compared with placebo. About 70% of carriers of the rs3798220 risk allele (C) have very high Lp(a) levels.

Accordingly, certain exemplary embodiments of the invention provide methods of using SNP rs3798220 (hCV25930271) for utilities related to HRT, such as methods of determining whether an individual will benefit from HRT based on which allele the individual possesses at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be identified as an individual who would benefit from HRT), methods of determining an individual's risk for CVD (particularly cardiovascular events such as MI) following HRT based on which allele the individual possesses at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be identified as an individual who would have a reduced risk for cardiovascular events such as MI following HRT as compared to the individual's risk for cardiovascular events in the absence of HRT (e.g., as compared with placebo)), and methods of treating an individual with HRT based on having identified that individual as someone who would be predicted to benefit from HRT (e.g., have a reduced risk for CVD, particularly cardiovascular events such as MI, following HRT) based on which allele they possess at SNP rs3798220 (e.g., if an individual possesses the rs3798220 risk allele (C), then that individual would be treated with HRT, since it would therefore be predicted that the individual would benefit from HRT), as well as other related methods.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for CVD such as CHD, particularly MI, or hypertension), or an individual's predicted drug responsiveness (e.g., response to statin treatment), based on assaying one or more SNPs disclosed herein, and/or an individual's allele(s)/genotype at one or more SNPs disclosed herein, etc.), and/or any other information pertaining to a test, may be referred to herein as a “report”. A tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as “reporting”, or as “providing” a report, “producing” a report, or “generating” a report).

Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a “secure database” that has security features that limit access to the report, such as to allow only the patient and the patient's medical practioners to view the report while preventing other unauthorized individuals from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).

A report can include, for example, an individual's risk for CVD, such as CHD (e.g., MI) or hypertension, or may just include the allele(s)/genotype that an individual carries at one or more SNPs disclosed herein, which may optionally be linked to information regarding the significance of having the allele(s)/genotype at the SNP (for example, a report on computer readable medium such as a network server may include hyperlink(s) to one or more journal publications or websites that describe the medical/biological implications, such as increased or decreased disease risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include disease risk or other medical/biological significance (e.g., drug responsiveness, etc.) as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including disease risk or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated disease risk or other medical/biological significance from a source outside of the report itself, such as from a medical practioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms may be used herein interchangeably), such as to the individual who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report. The act of “transmitting” or “communicating” a report can be by any means known in the art, based on the format of the report. Furthermore, “transmitting” or “communicating” a report can include delivering a report (“pushing”) and/or retrieving (“pulling”) a report. For example, reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically or in signal form (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (or other apparatus/devices such as biomedical devices or laboratory instrumentation) programmed to carry out the methods described herein. For example, in certain embodiments, the invention provides a computer programmed to receive (i.e., as input) the identity (e.g., the allele(s) or genotype at a SNP) of one or more SNPs disclosed herein and provide (i.e., as output) the disease risk (e.g., an individual's risk for CVD such as CHD, particularly MI, or hypertension) or other result (e.g., disease diagnosis or prognosis, drug responsiveness, etc.) based on the identity of the SNP(s). Such output (e.g., communication of disease risk, disease diagnosis or prognosis, drug responsiveness, etc.) may be, for example, in the form of a report on computer readable medium, printed in paper form, and/or displayed on a computer screen or other display.

In various exemplary embodiments, the invention further provides methods of doing business (with respect to methods of doing business, the terms “individual” and “customer” are used herein interchangeably). For example, exemplary methods of doing business can comprise assaying one or more SNPs disclosed herein and providing a report that includes, for example, a customer's risk for CVD such as CHD, particularly MI, or hypertension (based on which allele(s)/genotype is present at the assayed SNP(s)) and/or that includes the allele(s)/genotype at the assayed SNP(s) which may optionally be linked to information (e.g., journal publications, websites, etc.) pertaining to disease risk or other biological/medical significance such as by means of a hyperlink (the report may be provided, for example, on a computer network server or other computer readable medium that is internet-accessible, and the report may be included in a secure database that allows the customer to access their report while preventing other unauthorized individuals from viewing the report), and optionally transmitting the report. Customers (or another party who is associated with the customer, such as the customer's doctor, for example) can request/order (e.g., purchase) the test online via the internet (or by phone, mail order, at an outlet/store, etc.), for example, and a kit can be sent/delivered (or otherwise provided) to the customer (or another party on behalf of the customer, such as the customer's doctor, for example) for collection of a biological sample from the customer (e.g., a buccal swab for collecting buccal cells), and the customer (or a party who collects the customer's biological sample) can submit their biological samples for assaying (e.g., to a laboratory or party associated with the laboratory such as a party that accepts the customer samples on behalf of the laboratory, a party for whom the laboratory is under the control of (e.g., the laboratory carries out the assays by request of the party or under a contract with the party, for example), and/or a party that receives at least a portion of the customer's payment for the test). The report (e.g., results of the assay including, for example, the customer's disease risk and/or allele(s)/genotype at the assayed SNP(s)) may be provided to the customer by, for example, the laboratory that assays the SNP(s) or a party associated with the laboratory (e.g., a party that receives at least a portion of the customer's payment for the assay, or a party that requests the laboratory to carry out the assays or that contracts with the laboratory for the assays to be carried out) or a doctor or other medical practitioner who is associated with (e.g., employed by or having a consulting or contracting arrangement with) the laboratory or with a party associated with the laboratory, or the report may be provided to a third party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides the report to the customer. In further embodiments, the customer may be a doctor or other medical practitioner, or a hospital, laboratory, medical insurance organization, or other medical organization that requests/orders (e.g., purchases) tests for the purposes of having other individuals (e.g., their patients or customers) assayed for one or more SNPs disclosed herein and optionally obtaining a report of the assay results.

In certain exemplary methods of doing business, a kit for collecting a biological sample (e.g., a buccal swab for collecting buccal cells, or other sample collection device) is provided to a medical practitioner (e.g., a physician) which the medical practitioner uses to obtain a sample (e.g., buccal cells, saliva, blood, etc.) from a patient, the sample is then sent to a laboratory (e.g., a CLIA-certified laboratory) or other facility that tests the sample for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the patient's risk for CVD such as CHD, particularly MI, or hypertension), and the results of the test (e.g., the patient's genotype at one or more SNPs disclosed herein and/or the patient's disease risk based on their SNP genotype) are provided back to the medical practitioner (and/or directly to the patient and/or to another party such as a hospital, medical insurance company, genetic counselor, etc.) who may then provide or otherwise convey the results to the patient. The results are typically provided in the form of a report, such as described above.

In certain further exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells, or other sample collection device) are provided (e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy, general merchandise store, or any other desirable outlet), online via the internet, by mail order, etc., whereby customers can obtain (e.g., purchase) the kits, collect their own biological samples, and submit (e.g., send/deliver via mail) their samples to a laboratory (e.g., a CLIA-certified laboratory) or other facility which tests the samples for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the customer's risk for CVD such as CHD, particularly MI, or hypertension) and provides the results of the test (e.g., of the customer's genotype at one or more SNPs disclosed herein and/or the customer's disease risk based on their SNP genotype) back to the customer and/or to a third party (e.g., a physician or other medical practitioner, hospital, medical insurance company, genetic counselor, etc.). The results are typically provided in the form of a report, such as described above. If the results of the test are provided to a third party, then this third party may optionally provide another report to the customer based on the results of the test (e.g., the result of the test from the laboratory may provide the customer's genotype at one or more SNPs disclosed herein without disease risk information, and the third party may provide a report of the customer's disease risk based on this genotype result).

Certain further embodiments of the invention provide a system for determining an individual's CVD risk (e.g., risk for CHD, particularly MI, or hypertension), or whether an individual will benefit from statin treatment (or other therapy) in reducing CVD risk. Certain exemplary systems comprise an integrated “loop” in which an individual (or their medical practitioner) requests a determination of such individual's CVD risk (or drug response, such as response to statin treatment, etc.), this determination is carried out by testing a sample from the individual, and then the results of this determination are provided back to the requestor. For example, in certain systems, a sample (e.g., buccal cells, saliva, blood, etc.) is obtained from an individual for testing (the sample may be obtained by the individual or, for example, by a medical practitioner), the sample is submitted to a laboratory (or other facility) for testing (e.g., determining the genotype of one or more SNPs disclosed herein), and then the results of the testing are sent to the patient (which optionally can be done by first sending the results to an intermediary, such as a medical practioner, who then provides or otherwise conveys the results to the individual and/or acts on the results), thereby forming an integrated loop system for determining an individual's CVD risk (or drug response, etc.). The portions of the system in which the results are transmitted (e.g., between any of a testing facility, a medical practitioner, and/or the individual) can be carried out by way of electronic or signal transmission (e.g., by computer such as via e-mail or the internet, by providing the results on a website or computer network server which may optionally be a secure database, by phone or fax, or by any other wired or wireless transmission methods known in the art). Optionally, the system can further include a risk reduction component (i.e., a disease management system) as part of the integrated loop (for an example of a disease management system, see U.S. Pat. No. 6,770,029, “Disease management system and method including correlation assessment”). For example, the results of the test can be used to reduce the risk of the disease in the individual who was tested, such as by implementing a preventive therapy regimen (e.g., administration of a drug regimen such as a statin treatment for reducing CVD risk), modifying the individual's diet, increasing exercise, reducing stress, and/or implementing any other physiological or behavioral modifications in the individual with the goal of reducing disease risk. For reducing CVD risk (e.g., risk for CHD, particularly MI, or hypertension), this may include any means used in the art for improving aspects of an individual's health relevant to reducing CVD risk. Thus, in exemplary embodiments, the system is controlled by the individual and/or their medical practioner in that the individual and/or their medical practioner requests the test, receives the test results back, and (optionally) acts on the test results to reduce the individual's disease risk, such as by implementing a disease management system.

The various methods described herein, such as correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for CVD such as CHD, particularly MI, or hypertension (and/or correlating the presence or absence of a polymorphism with the predicted response of an individual to a drug such as a statin), can be carried out by automated methods such as by using a computer (or other apparatus/devices such as biomedical devices, laboratory instrumentation, or other apparatus/devices having a computer processor) programmed to carry out any of the methods described herein. For example, computer software (which may be interchangeably referred to herein as a computer program) can perform the step of correlating the presence or absence of a polymorphism in an individual with an altered (e.g., increased or decreased) risk (or no altered risk) for CVD (particularly risk for CHD, such as MI, or hypertension) for the individual. Computer software can also perform the step of correlating the presence or absence of a polymorphism in an individual with the predicted response of the individual to a drug such as a statin. Accordingly, certain embodiments of the invention provide a computer (or other apparatus/device) programmed to carry out any of the methods described herein.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with CVD (particularly CHD, especially MI, or hypertension), including the transcript sequences (SEQ ID NOS:1-307), genomic sequences (SEQ ID NOS:1015-1400), and protein sequences (SEQ ID NOS:308-614) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5′) plus 100 nucleotides downstream (3′) of each SNP position (SEQ ID NOS:615-1014 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:1401-4006 and 5414 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc.

Isolated Nucleic Acid Molecules

The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1 and 2 may be interchangeably referred to throughout the present text as “SNP-containing nucleic acid molecules.” Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled “SNP Detection Reagents”), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.

As used herein, an “isolated nucleic acid molecule” generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered “isolated.” Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered “isolated.” For example, recombinant DNA molecules contained in a vector are considered “isolated.” Further examples of “isolated” DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such instances the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.

An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are referred to in Table 1 and provided in the Sequence Listing (SEQ ID NOS:1-307), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS:1015-1400). Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.

Thus, the present invention also encompasses fragments of the nucleic acid sequences as disclosed in Tables 1 and 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414) and their complements. The actual sequences referred to in the tables are provided in the Sequence Listing. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides. Furthermore, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any other number in between). The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H. A. Erlich, Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077 (1988)), strand displacement amplification (SDA) (U.S. Pat. Nos. 5,270,184 and 5,422,252), transcription-mediated amplification (TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat. No. 6,027,923) and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA) and self-sustained sequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874 (1990)). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5′ and 3′ to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is a SNP-containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.

Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, 300, 400, or 500 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically up to about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600-700 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1 and 2. Such a product may have additional sequences on its 5′ end or 3′ end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g., at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product. However, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences referred to in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.

The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-307, genomic sequences are referred to in Table 2 as SEQ ID NOS:1015-1400, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:615-1014, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:308-614). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5′ and 3′ sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675; 5,623,049; and 5,714,331. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule. Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art. See, e.g., Corey, “Peptide nucleic acids: expanding the scope of nucleic acid recognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup et al., “Peptide nucleic acids (PNA): synthesis, properties and potential applications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters 4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal Chemistry Letters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272 (2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP-containing nucleic acid molecules, SNP detection reagents (e.g., probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1 and 2). Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and 2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences referred to and shown in Tables 1 and 2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences referred to in Table 1.

To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Computational Molecular Biology, A. M. Lesk, ed., Oxford University Press, N.Y (1988); Biocomputing: Informatics and Genome Projects, D. W. Smith, ed., Academic Press, N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin, eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology, G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence Analysis Primer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y. (1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (J Mol Biol (48):444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J. Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention can further be used as a “query sequence” to perform a search against sequence databases; for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res 25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) and KERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December 2002)). For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5′ untranslated regions (UTRs), 3′ untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (referred to in Table 1 as SEQ ID NOS:1-307), genomic sequences (referred to in Table 2 as SEQ ID NOS:1015-1400), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:1401-4006 and 5414), can be used for the design of SNP detection reagents. The actual sequences referred to in the tables are provided in the Sequence Listing. As used herein, a “SNP detection reagent” is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined). Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs referred to in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5′ and/or 3′ to a SNP position, particularly a region corresponding to the context sequences referred to in Table 1 and/or Table 2 (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414). Another example of a detection reagent is a primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.

In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g., arrays or beads) or supplied in solution (e.g. probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5′ and/or 3′ to the SNP position to carry out the desired assay.

Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS:1-307), genomic sequences (SEQ ID NOS:1015-1400), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:615-1014; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS:1401-4006 and 5414) disclosed in the Sequence Listing and in Tables 1 and 2. The actual sequences referred to in the tables are provided in the Sequence Listing. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.

In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm that starts at the 5′ or at the 3′ end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.

A primer or probe of the present invention is typically at least about 8 nucleotides in length. In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as “allele-specific oligonucleotides,” “allele-specific probes,” or “allele-specific primers.” The design and use of allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection: A Practical Approach, Cotton et al., eds., Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele-specific probe are as follows: prehybridization with a solution containing 5× standard saline phosphate EDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2×SSPE, and 0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used for allele-specific primer extension reactions with a solution containing, e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may be carried out at an elevated temperature such as 60° C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g., alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele. While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g., a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5′ most end or the 3′ most end of the probe or primer. In a specific preferred embodiment that is particularly suitable for use in a oligonucleotide ligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of the probe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are not limited to, the phosphotriester method described by Narang et al., Methods in Enzymology 68:90 (1979); the phosphodiester method described by Brown et al., Methods in Enzymology 68:109 (1979); the diethylphosphoamidate method described by Beaucage et al., Tetrahedron Letters 22:1859 (1981); and the solid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448 (1989). Typically, the primer's 3′-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3′-most position of the oligonucleotide (i.e., the 3′-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below.

In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3′-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3′-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self-quenching probe such as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res 25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3′-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also contemplated by the present invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms “kits” and “systems,” as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g. TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip” systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g. a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in Chee et al., U.S. Pat. No. 5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., Nat Biotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci 93:10614-10619 (1996), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteo et al., “New chips for molecular biology and diagnostics,” Biotechnol Annu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications,” Psychiatr Genet 12(4):181-92 (December 2002); Heller, “DNA microarray technology: devices, systems, and applications,” Annu Rev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al., “Analysis of SNPs and other genomic variations using gel-based chips,” Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-density genechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol 77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.

A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-30 nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5′ or 3′ sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g., specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g., typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y. (1989).

In other embodiments, the arrays are used in conjunction with chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection. U.S. patent applications that describe chemiluminescent approaches for microarray detection: Ser. Nos. 10,620,332 and 10,620,333. U.S. patents that describe methods and compositions of dioxetane for performing chemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024; 5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. And the U.S. published application that discloses methods and compositions for microarray controls: US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in-between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a “gridded” array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.

Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.

A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells), biopsies, buccal swabs or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparation system, and Roche Molecular Systems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is a compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser-induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art. See, e.g., Weigl et al., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev 55(3):349-77 (February 2003). In such microfluidic devices, the containers may be referred to as, for example, microfluidic “compartments,” “chambers,” or “channels.”

Microfluidic devices, which may also be referred to as “lab-on-a-chip” systems, biomedical micro-electro-mechanical systems (bioMEMs), or multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro-machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Pat. No. 6,153,073, Dubrow et al., and U.S. Pat. No. 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3′ end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety of uses, especially for the diagnosis, prognosis, treatment, and prevention of CVD (particularly CHD, such as MI, or hypertension). For example, the nucleic acid molecules of the invention are useful for predicting an individual's risk for developing CVD (particularly the risk for CHD, especially MI, or hypertension), for prognosing the progression of CVD (e.g., the severity or consequences of CHD, particularly MI, or hypertension) in an individual, in evaluating the likelihood of an individual who has CVD (or who is at increased risk for CVD) of responding to treatment (or prevention) of CVD with a particular therapeutic agent, and/or predicting the likelihood that the individual will experience toxicity or other undesirable side effects from a treatment, etc. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.

A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule referred to in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphism(s) is at risk for developing CVD (or has already developed early stage CVD), or the likelihood that an individual will respond positively to a treatment (including preventive treatment) for CVD such as a particular therapeutic agent. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to the disease.

Furthermore, the nucleic acid molecules of the invention are therefore useful for detecting a gene (gene information is disclosed in Table 2, for example) which contains a SNP disclosed herein and/or products of such genes, such as expressed mRNA transcript molecules (transcript information is disclosed in Table 1, for example), and are thus useful for detecting gene expression. The nucleic acid molecules can optionally be implemented in, for example, an array or kit format for use in detecting gene expression.

The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences referred to in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.

The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g., an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.

The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.

The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allows, for example, effective clinical design of treatment compounds and dosage regimens.

The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.

The nucleic acid molecules of the invention are also useful in gene therapy in patients whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual.

SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each of one or more SNP positions (such as a SNP position disclosed in Table 1 and/or Table 2), for either or both alleles, may be referred to by such phrases as SNP genotyping, determining the “identity” of a SNP, determining the “content” of a SNP, or determining which nucleotide(s)/allele(s) is/are present at a SNP position. Thus, these terms can refer to detecting a single allele (nucleotide) at a SNP position or can encompass detecting both alleles (nucleotides) at a SNP position (such as to determine the homozygous or heterozygous state of a SNP position). Furthermore, these terms may also refer to detecting an amino acid residue encoded by a SNP (such as alternative amino acid residues that are encoded by different codons created by alternative nucleotides at a SNP position).

The present invention provides methods of SNP genotyping, such as for use in evaluating an individual's risk for developing CVD (particularly CHD, such as MI, or hypertension), for evaluating an individual's prognosis for disease severity and recovery, for predicting the likelihood that an individual who has previously had CVD (such as CHD, particularly MI, or hypertension) will have a recurrence of CVD again in the future, for implementing a preventive or treatment regimen for an individual based on that individual having an increased susceptibility for developing CVD (e.g., increased risk for CHD, particularly MI, or hypertension), in evaluating an individual's likelihood of responding to a therapeutic treatment (particularly for treating or preventing CVD), in selecting a treatment or preventive regimen (e.g., in deciding whether or not to administer a particular therapeutic agent to an individual having CVD, or who is at increased risk for developing CVD in the future), or in formulating or selecting a particular treatment or preventive regimen such as dosage and/or frequency of administration of a therapeutic agent or choosing which form/type of a therapeutic agent to be administered, such as a particular pharmaceutical composition or compound, etc.), determining the likelihood of experiencing toxicity or other undesirable side effects from a treatment, or selecting individuals for a clinical trial of a therapeutic agent (e.g., selecting individuals to participate in the trial who are most likely to respond positively to a therapeutic agent and/or excluding individuals from the trial who are unlikely to respond positively to a therapeutic agent based on their SNP genotype(s), or selecting individuals who are unlikely to respond positively to a particular therapeutic agent based on their SNP genotype(s) to participate in a clinical trial of another therapeutic agent that may benefit them), etc.

Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region (e.g., SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., “Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput,” Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of single nucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003); Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes,” Am J Pharmacogenomics 2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu Rev Genomics Hum Genet 2:235-58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, “High-throughput SNP analysis for genetic association studies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.

Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al., Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); and Hayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and 51 protection or chemical cleavage methods.

In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5′ most and the 3′ most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5′ or 3′ most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. It will be apparent to one of skill in the art that such primers and probes for detecting the SNPs of the present invention are useful in, for example, screening for individuals who are susceptible to developing CVD (particularly CHD, such as MI, or hypertension) and related pathologies, or in screening individuals who have CVD (or who are susceptible to CVD) for their likelihood of responding to a particular treatment (e.g., a particular therapeutic agent). These probes and primers can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3′ most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3′ to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3′ most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA. The following U.S. patents describe OLA strategies for performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148; 5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array. U.S. application US01/17329 (and Ser. No. 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout. U.S. applications 60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI-TOF (Matrix Assisted Laser Desorption Ionization—Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.

Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5′) from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3′ end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3′ end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5′ side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al., “A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,” Rapid Commun Mass Spectrom 17(11):1195-202 (2003).

The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, “SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry,” Bioinformatics 19 Suppl 1:144-153 (July 2003); Storm et al., “MALDI-TOF mass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62 (2003); Jurinke et al., “The use of Mass ARRAY technology for high throughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al., “Automated genotyping using the DNA MassArray technology,” Methods Mol Biol 187:179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized (e.g. Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv Chromatogr 36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol 38:147-159 (1993). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730xl DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.

Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). Myers et al., Nature 313:495 (1985). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products are related to base-sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence-dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel. PCR Technology: Principles and Applications for DNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y. (1992).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on an individual's genotype (“pharmacogenomics”), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent, predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent, and human identification applications such as forensics.

Analysis of Genetic Associations Between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (pharmacogenomics), drug toxicity screening, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies. Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disease is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disease in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disease, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disease are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.

In both types of observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disease and the disease itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with diseases and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.

After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy-Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy-Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disease. B. Weir, Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3×2 table (3 genotypes×2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, −1, −1), additive or allelic (with contrast coefficients 1, 0, −1) and recessive (with contrast coefficients 1, 1, −2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.

In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran-Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, getting a certain disease or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley (2000). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.

In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together. Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disease-causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disease is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker-marker linkage disequilibrium measures, both D′ and r², are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Daly et al, Nature Genetics 29:232-235 (2001). Haplotype association with the disease status can be performed using such blocks once they have been elucidated.

Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed that score tests can be done on haplotypes using the program “haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.

An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the P value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted P value <0.2 (a significance level on the lenient side), for example, may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disease. It is preferred that a p-value <0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disease. It is more preferred that a p-value <0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wide error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate. Westfall et al., Multiple comparisons and multiple tests, SAS Institute (1999). Permutation tests to control for the false discovery rates, FDR, can be more powerful. Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57:1289-1300 (1995); Westfall and Young, Resampling-based Multiple Testing, Wiley (1993). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.

In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then be performed by combining evidence of different studies. Modern Epidemiology 643-673, Lippincott, Williams & Wilkins (1998). If available, association results known in the art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disease classification error rates.

It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies when prevalence of the disease is associated with different subpopulation groups. Ewens and Spielman, Am J Hum Genet 62:450-458 (1995). Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder can be used to adjust for the inflation of test statistics due to population stratification. Devlin et al., Biometrics 55:997-1004 (1999). The GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs. Devlin et al., Genet Epidem 21:273-284 (2001).

While Pritchard's method recommended using 15-20 unlinked microsatellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000). Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been found for the predisposition to disease, the next step is to set up a classification/prediction scheme to predict the category (for instance, disease or no-disease) that an individual will be in depending on his genotypes of associated SNPs and other non-genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks. Draper and Smith, Applied Regression Analysis, Wiley (1998). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods. The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes and disease-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disease for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with serious disease in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disease, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development of CVD (e.g., CHD, such as MI, or hypertension), or to responsiveness of an individual to a therapeutic treatment, in different ways. Some polymorphisms occur within a protein coding sequence and contribute to disease phenotype by affecting protein structure. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics” include, but are not limited to, any of the following: detection of CVD (such as CHD, e.g. MI, or hypertension) that an individual may presently have, predisposition/susceptibility/predictive screening (i.e., determining whether an individual has an increased or decreased risk of developing CVD in the future), prognosing the future course of CVD or recurrence of CVD in an individual, determining a particular type or subclass of CVD in an individual who currently or previously had CVD, confirming or reinforcing a previously made diagnosis of CVD, evaluating an individual's likelihood of responding positively to a particular treatment or therapeutic agent (particularly treatment or prevention of CVD), determining or selecting a therapeutic or preventive strategy that an individual is most likely to positively respond to (e.g., selecting a particular therapeutic agent or combination of therapeutic agents, or determining a dosing regimen, etc.), classifying (or confirming/reinforcing) an individual as a responder/non-responder (or determining a particular subtype of responder/non-responder) with respect to the individual's response to a drug treatment, and predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound. Such diagnostic uses can be based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g., alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in “linkage equilibrium.” In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.

Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e., in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site is found to be useful for, for example, predicting an individual's susceptibility to CVD or an individual's response to a treatment, then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for the same purposes. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g., CVD, or responder/non-responder to a drug treatment) that is influenced by the causative SNP(s). Therefore, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.

Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the causative/associated SNP, other SNPs in the same intergenic region as the causative/associated SNP, SNPs that are outside but near a gene (e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) that harbors a causative/associated SNP, etc. Such useful LD SNPs can be selected from among the SNPs disclosed in Tables 1 and 2, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al., “Haplotype blocks and linkage disequilibrium in the human genome,” Nat Rev Genet 4(8):587-97 (August 2003); Garner et al., “On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci,” Genet Epidemiol 24(1):57-67 (January 2003); Ardlie et al., “Patterns of linkage disequilibrium in the human genome,” Nat Rev Genet 3(4):299-309 (April 2002); erratum in Nat Rev Genet 3(7):566 (July 2002); and Remm et al., “High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (February 2002); J. B. S. Haldane, “The combination of linkage values, and the calculation of distances between the loci of linked factors,” J Genet 8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of the Natural History Society of Brünn) (1866); Genes IV, B. Lewin, ed., Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. Clark Principles of Population Genetics 2^(nd) ed., Sinauer Associates, Inc., Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide. 2^(nd) ed., Johns Hopkins University Press (2004); R. C. Lewontin, “The interaction of selection and linkage. I. General considerations; heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction to Mathematical Statistics 2^(nd) ed., John Wiley & Sons, Inc., N.Y. (1954); R. R. Hudson, “Two-locus sampling distributions and their application,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M. Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EM algorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin, “Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet, S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm,” Ann Hum Genet 68(Pt 2):165-177 (2004); A. D. Long and C. H. Langley C H, “The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits,” Genome Research 9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley & Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methods for Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); The International HapMap Consortium, “The International HapMap Project,” Nature 426:789-796 (2003); The International HapMap Consortium, “A haplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A. Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The International HapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G. McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human genetic variation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005); J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies for common diseases and complex traits,” Nat Genet 6:95-108 (2005); S. J. Schrodi, “A probabilistic approach to large-scale association scans: a semi-Bayesian method to detect disease-predisposing alleles,” SAGMB 4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd, “Genome-wide association studies: theoretical and practical concerns,” Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkage disequilibrium in humans: models and data,” Am J Hum Genet 69:1-14 (2001).

As discussed above, one aspect of the present invention is the discovery that SNPs that are in certain LD distance with an interrogated SNP can also be used as valid markers for determining whether an individual has an increased or decreased risk of having or developing CVD, for example. As used herein, the term “interrogated SNP” refers to SNPs that have been found to be associated with an increased or decreased risk of disease using genotyping results and analysis, or other appropriate experimental method as exemplified in the working examples described in this application. As used herein, the term “LD SNP” refers to a SNP that has been characterized as a SNP associating with an increased or decreased risk of diseases due to their being in LD with the “interrogated SNP” under the methods of calculation described in the application. Below, applicants describe the methods of calculation with which one of ordinary skilled in the art may determine if a particular SNP is in LD with an interrogated SNP. The parameter r² is commonly used in the genetics art to characterize the extent of linkage disequilibrium between markers (Hudson, 2001). As used herein, the term “in LD with” refers to a particular SNP that is measured at above the threshold of a parameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sample of chromosomes obtained from a population. Suppose one has genotype data at two genetic markers located on the same chromosome, for the markers A and B. Further suppose that two alleles segregate at each of these two markers such that alleles A₁ and A₂ can be found at marker A and alleles B₁ and B₂ at marker B. Also assume that these two markers are on a human autosome. If one is to examine a specific individual and find that they are heterozygous at both markers, such that their two-marker genotype is A₁A₂B₁B₂, then there are two possible configurations: the individual in question could have the alleles A₁B₁ on one chromosome and A₂B₂ on the remaining chromosome; alternatively, the individual could have alleles A₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleles on a chromosome is called a haplotype. In this illustration, the individual could have haplotypes/A₂B₂ or A₁B₂/A₂B₁ (see Hartl and Clark (1989) for a more complete description). The concept of linkage equilibrium relates the frequency of haplotypes to the allele frequencies.

Assume that a sample of individuals is selected from a larger population. Considering the two markers described above, each having two alleles, there are four possible haplotypes: A₁B₁, A₁/B₂, A₂B₁ and A₂B₂. Denote the frequencies of these four haplotypes with the following notation. P ₁₁=freq(A ₁ B ₁)  (1) P ₁₂=freq(A ₁ B ₂)  (2) P ₂₁=freq(A ₂ B ₁)  (3) P ₂₂=freq(A ₂ B ₂)  (4) The allele frequencies at the two markers are then the sum of different haplotype frequencies, it is straightforward to write down a similar set of equations relating single-marker allele frequencies to two-marker haplotype frequencies: p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5) p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6) q ₁=freq(B ₁)=P ₁₁ +P ₂₁  (7) q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8) Note that the four haplotype frequencies and the allele frequencies at each marker must sum to a frequency of 1. P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9) p ₁ +p ₂=1  (10) q ₁ +q ₂=1  (11) If there is no correlation between the alleles at the two markers, one would expect that the frequency of the haplotypes would be approximately the product of the composite alleles. Therefore, P ₁₁ ≈p ₁ q ₁  (12) P ₁₂ ≈p ₁ q ₂  (13) P ₂₁ ≈p ₂ q ₁  (14) P ₂₂ ≈p ₂ q ₂  (15) These approximating equations (12)-(15) represent the concept of linkage equilibrium where there is independent assortment between the two markers—the alleles at the two markers occur together at random. These are represented as approximations because linkage equilibrium and linkage disequilibrium are concepts typically thought of as properties of a sample of chromosomes; and as such they are susceptible to stochastic fluctuations due to the sampling process. Empirically, many pairs of genetic markers will be in linkage equilibrium, but certainly not all pairs.

Having established the concept of linkage equilibrium above, applicants can now describe the concept of linkage disequilibrium (LD), which is the deviation from linkage equilibrium. Since the frequency of the A₁B₁ haplotype is approximately the product of the allele frequencies for A₁ and B₁ under the assumption of linkage equilibrium as stated mathematically in (12), a simple measure for the amount of departure from linkage equilibrium is the difference in these two quantities, D, D=P ₁₁ −p ₁ q ₁  (16) D=0 indicates perfect linkage equilibrium. Substantial departures from D=0 indicates LD in the sample of chromosomes examined. Many properties of D are discussed in Lewontin (1964) including the maximum and minimum values that D can take. Mathematically, using basic algebra, it can be shown that D can also be written solely in terms of haplotypes: D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17) If one transforms D by squaring it and subsequently dividing by the product of the allele frequencies of A₁, A₂, B₁ and B₂, the resulting quantity, called r², is equivalent to the square of the Pearson's correlation coefficient commonly used in statistics (e.g. Hoel, 1954).

$\begin{matrix} {r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18) \end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium between the two markers examined in the sample set. As values of r² increase, the two markers are said to be in linkage disequilibrium. The range of values that r² can take are from 0 to 1. r²=1 when there is a perfect correlation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And as such, it is necessary to formulate notation specific to the samples studied. In the approach discussed here, three types of samples are of primary interest: (i) a sample of chromosomes from individuals affected by a disease-related phenotype (cases), (ii) a sample of chromosomes obtained from individuals not affected by the disease-related phenotype (controls), and (iii) a standard sample set used for the construction of haplotypes and calculation pairwise linkage disequilibrium. For the allele frequencies used in the development of the method described below, an additional subscript will be added to denote either the case or control sample sets. p _(1,cs)=freq(A ₁ in cases)  (19) p _(2,cs)=freq(A ₂ in cases)  (20) q _(1,cs)=freq(B ₁ in cases)  (21) q _(2,cs)=freq(B ₂ in cases)  (22) Similarly, p _(1,ct)=freq(A ₁ in controls)  (23) P _(2,ct)=freq(A ₂ in controls)  (24) q _(1,ct)=freq(B ₁ in controls)  (25) q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkage disequilibrium calculations, data obtained from the International HapMap project (The International HapMap Consortium 2003, 2005; Thoris son et al, 2005; McVean et al, 2005) can be used for the calculation of pairwise r² values. Indeed, the samples genotyped for the International HapMap Project were selected to be representative examples from various human sub-populations with sufficient numbers of chromosomes examined to draw meaningful and robust conclusions from the patterns of genetic variation observed. The International HapMap project website (hapmap.org) contains a description of the project, methods utilized and samples examined. It is useful to examine empirical data to get a sense of the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above. However, knowing the 2-marker haplotype frequencies requires that phase to be determined for doubly heterozygous samples. When phase is unknown in the data examined, various algorithms can be used to infer phase from the genotype data. This issue was discussed earlier where the doubly heterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have one of two different sets of chromosomes: A₁B₁/A₂B₂ or A₁B₂/A₂. One such algorithm to estimate haplotype frequencies is the expectation-maximization (EM) algorithm first formalized by Dempster et al. (1977). This algorithm is often used in genetics to infer haplotype frequencies from genotype data (e.g. Excoffier and Slatkin (1995); Tregouet et al. (2004)). It should be noted that for the two-SNP case explored here, EM algorithms have very little error provided that the allele frequencies and sample sizes are not too small. The impact on r² values is typically negligible.

As correlated genetic markers share information, interrogation of SNP markers in LD with a disease-associated SNP marker can also have sufficient power to detect disease association (Long and Langley (1999)). The relationship between the power to directly find disease-associated alleles and the power to indirectly detect disease-association was investigated by Pritchard and Przeworski (2001). In a straight-forward derivation, it can be shown that the power to detect disease association indirectly at a marker locus in linkage disequilibrium with a disease-association locus is approximately the same as the power to detect disease-association directly at the disease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$ (the reciprocal of equation 18) at the marker in comparison with the disease-association locus.

Therefore, if one calculated the power to detect disease-association indirectly with an experiment having N samples, then equivalent power to directly detect disease-association (at the actual disease-susceptibility locus) would necessitate an experiment using approximately r²N samples. This elementary relationship between power, sample size and linkage disequilibrium can be used to derive an r² threshold value useful in determining whether or not genotyping markers in linkage disequilibrium with a SNP marker directly associated with disease status has enough power to indirectly detect disease-association.

To commence a derivation of the power to detect disease-associated markers through an indirect process, define the effective chromosomal sample size as

$\begin{matrix} {{n = \frac{4\; N_{cs}N_{ct}}{N_{cs} + N_{ct}}};} & (27) \end{matrix}$ where N_(cs) and N_(ct) are the numbers of diploid cases and controls, respectively. This is necessary to handle situations where the numbers of cases and controls are not equivalent. For equal case and control sample sizes, N_(cs)=N_(ct)=N, the value of the effective number of chromosomes is simply n=2N—as expected. Let power be calculated for a significance level α (such that traditional P-values below α will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(•). Mathematically,

$\begin{matrix} {{\Phi(x)} = {\frac{1}{\sqrt{2\;\pi}}{\int_{- \infty}^{x}{e^{- \frac{\theta^{2}}{2}}\ d\;\theta}}}} & (28) \end{matrix}$ Alternatively, the following error function notation (Erf) may also be used,

$\begin{matrix} {{{\Phi(x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}}\;} & (29) \end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield a pre-specified minimum amount of power to detect disease association though indirect interrogation. Noting that the LD SNP marker could be the one that is carrying the disease-association allele, therefore that this approach constitutes a lower-bound model where all indirect power results are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associated markers. Therefore, 1−β is the classical definition of statistical power. Substituting the Pritchard-Pzreworski result into the sample size, the power to detect disease association at a significance level of α is given by the approximation

$\begin{matrix} {{{1 - \beta} \cong {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}};} & (30) \end{matrix}$ where Z_(u) is the inverse of the standard normal cumulative distribution evaluated at u (u∈(0,1)). Z_(u)=Φ⁻¹(u), where Φ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore 1−α/2=0.975, one obtains Z_(0.975)=1.95996. Next, setting power equal to a threshold of a minimum power of T,

$\begin{matrix} {T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}} & (31) \end{matrix}$ and solving for r², the following threshold r² is obtained:

$\begin{matrix} {r_{T}^{2} = {\frac{\left\lbrack {q_{1,{cs}} - \left( {1 - q_{1,{cs}}} \right) + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rbrack}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - {\alpha/2}}} \right\rbrack}^{2}} & (32) \\ {{Or},} & \; \\ {r_{T}^{2} = {\frac{\left( {Z_{T} + Z_{1 - {\alpha/2}}} \right)^{2}}{n}\left\lbrack \frac{{q_{1,{cs}}\left( q_{1,{cs}} \right)}^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{1,{ct}}} \right)^{2}} \right\rbrack}} & (33) \end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a number of other SNPs with varying levels of LD with the interrogated SNP. The threshold value r_(T) ² is the minimum value of linkage disequilibrium between the interrogated SNP and the potential LD SNPs such that the LD SNP still retains a power greater or equal to T for detecting disease-association. For example, suppose that SNP rs200 is genotyped in a case-control disease-association study and it is found to be associated with a disease phenotype. Further suppose that the minor allele frequency in 1,000 case chromosomes was found to be 16% in contrast with a minor allele frequency of 10% in 1,000 control chromosomes. Given those measurements one could have predicted, prior to the experiment, that the power to detect disease association at a significance level of 0.05 was quite high—approximately 98% using a test of allelic association. Applying equation (32) one can calculate a minimum value of r² to indirectly assess disease association assuming that the minor allele at SNP rs200 is truly disease-predisposing for a threshold level of power. If one sets the threshold level of power to be 80%, then r_(T) ²=0.489 given the same significance level and chromosome numbers as above. Hence, any SNP with a pairwise r² value with rs200 greater than 0.489 is expected to have greater than 80% power to detect the disease association. Further, this is assuming the conservative model where the LD SNP is disease-associated only through linkage disequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypes with disease phenotypes, such as CVD, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as CVD, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with CVD might indicate a probability of 20% that an individual has or is at risk of developing CVD, whereas detection of five SNPs, each of which correlates with CVD, might indicate a probability of 80% that an individual has or is at risk of developing CVD. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of CVD, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors.

It will be understood by practitioners skilled in the treatment or diagnosis of CVD that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) of developing CVD, and/or pathologies related to CVD, but rather to indicate a certain increased (or decreased) degree or likelihood of developing the disease based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments or to allow an individual carrying one or more significant SNPs or SNP haplotypes to foresee warning signs such as minor clinical symptoms, or to have regularly scheduled physical exams to monitor for appearance of a condition in order to identify and begin treatment of the condition at an early stage. Particularly with diseases that are extremely debilitating or fatal if not treated on time, the knowledge of a potential predisposition, even if this predisposition is not absolute, would likely contribute in a very significant manner to treatment efficacy.

The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids. The trait analyzed using the diagnostics of the invention may be any detectable trait that is commonly observed in pathologies and disorders related to CVD.

Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the “gene response” of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods of assaying (i.e., testing) one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a therapeutic or preventive agent to the individual based on the allele(s) present at the SNP(s) having indicated that the individual can benefit from the therapeutic or preventive agent.

In further aspects of the invention, there are provided methods of assaying one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a diagnostic agent (e.g., an imaging agent), or otherwise carrying out further diagnostic procedures on the individual, based on the allele(s) present at the SNP(s) having indicated that the diagnostic agents or diagnostics procedures are justified in the individual.

In yet other aspects of the invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g., a small molecule drug, antibody, peptide, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to an individual who has been tested for one or more SNPs provided by the present invention.

Pharmacogenomics

The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent or pharmaceutical compound, or to a class of such compounds. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001); Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); and Linder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.

As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in predicting an individual's predisposition to CVD (e.g., CHD, such as MI, or hypertension) and in predicting an individual's responsiveness to a drug (particularly for treating or preventing CVD). Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et al., Trends in Biotechnology, August 2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al., “Pharmacogenetic analysis of clinically relevant genetic polymorphisms,” Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med 34(5):357-79 (2002); Maimone et al., “Pharmacogenomics of neurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February 2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (December 1999). Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., “Pharmacogenomics of drugs affecting the cardiovascular system,” Clin Chem Lab Med 41(4):590-9 (April 2003); Mukherjee et al., “Pharmacogenomics in cardiovascular diseases,” Prog Cardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et al., “Cardiovascular pharmacogenetics in the SNP era,” J Thromb Haemost 1(7):1398-402 (July 2003). Pharmacogenomics as it relates to cancer is discussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, and the individual patient,” Cancer Invest 21(4):630-40 (2003); and Watters et al., “Cancer pharmacogenomics: current and future applications,” Biochim Biophys Acta 1603(2):99-111 (March 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of using the SNPs disclosed herein to identify or stratify patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent.

For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype, such as selecting individuals for inclusion in a clinical trial and/or assigning individuals to a particular group within a clinical trial (e.g., an “arm” or “cohort” of the trial). For example, individuals with SNP genotypes that indicate that they are likely to positively respond to a drug can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or who are at risk for suffering toxic effects or other adverse reactions, can be excluded from the clinical trials. This not only can improve the safety of clinical trials, but also can enhance the chances that the trial will demonstrate statistically significant efficacy.

Thus, certain embodiments of the invention provide methods for conducting a clinical trial of a therapeutic agent in which a human is selected for inclusion in the clinical trial and/or assigned to a particular group within a clinical trial based on the presence or absence of one or more SNPs disclosed herein. In certain embodiments, the therapeutic agent is a statin.

In certain exemplary embodiments, SNPs of the invention can be used to select individuals who are unlikely to respond positively to a particular therapeutic agent (or class of therapeutic agents) based on their SNP genotype(s) to participate in a clinical trial of another type of drug that may benefit them. Thus, in certain embodiments, the SNPs of the invention can be used to identify patient populations who do not adequately respond to current treatments and are therefore in need of new therapies. This not only benefits the patients themselves, but also benefits organizations such as pharmaceutical companies by enabling the identification of populations that represent markets for new drugs, and enables the efficacy of these new drugs to be tested during clinical trials directly in individuals within these markets.

The SNP-containing nucleic acid molecules of the present invention are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of a variant gene, or encoded product, particularly in a treatment regimen or in clinical trials. Thus, the gene expression pattern can serve as an indicator for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance, as well as an indicator for toxicities. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant.

Furthermore, the SNPs of the present invention may have utility in determining why certain previously developed drugs performed poorly in clinical trials and may help identify a subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby “rescuing” previously developed drugs, and enabling the drug to be made available to a particular CVD patient population that can benefit from it.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify novel therapeutic targets for CVD. For example, genes containing the disease-associated variants (“variant genes”) or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disease or prevent or delay disease onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.

The invention further provides methods for identifying a compound or agent that can be used to treat CVD. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell-free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.

Variant gene expression in a CVD patient can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g., mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as CVD that is characterized by variant gene expression (e.g., either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the CVD-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating or preventing CVD or related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.

In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70-kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences 18^(th) ed., E. W. Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80% wt.

Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of a CVD-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different CVD-associated protein to thereby counteract the effects of CVD.

For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology: Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). An antisense nucleic acid molecule is generally designed to be complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g., RNaseH or RNase L) that cleave the target RNA. Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates. See, e.g., Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g., in gene knock-out or knock-down experiments).

Antisense technology is further reviewed in: Lavery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al., “Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther 5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvement through novel chemical modifications,” Eur J Biochem 270(8):1628-44 (April 2003); Dias et al., “Antisense oligonucleotides: basic concepts and mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen, “Clinical development of antisense oligonucleotides as anti-cancer therapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisense anticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets 1(3):177-96 (November 2001); and Bennett, “Efficiency of antisense oligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev 12(3):215-24 (June 2002).

The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g., SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g., a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g., an alternative SNP nucleotide that encodes a protein having normal function).

Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as CVD, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.

The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21, 22, or 23 nucleotides in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917 (2002). Accordingly, an aspect of the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21, 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi. Because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g., for turning off defective, disease-causing genes), and are also useful for characterizing and validating gene function (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds et al., “Rational siRNA design for RNA interference,” Nat Biotechnol 22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewide view of gene silencing by small interfering RNAs,” PNAS 100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” J Biol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms and their potential use for therapy,” Curr Opin Chem Biol 6(6):829-34 (December 2002); Lavery et al., “Antisense and RNAi: powerful tools in drug target discovery and validation,” Curr Opin Drug Discov Devel 6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” Trends Genet 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing in therapeutic intervention,” Drug Discovery Today 7(20):1040-1046 (October 2002); McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia et al., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June 1999).

Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, and development, and thus the SNPs of the present invention are useful for improving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population. Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and development process. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).

Knowledge of variants (e.g., SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g., a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants. Rothberg, Nat Biotechnol 19(3):209-11 (March 2001). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.

Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (March 2002).

Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1 and 2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1, thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1 and 2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.

A subject suffering from a pathological condition ascribed to a SNP, such as CVD, may be treated so as to correct the genetic defect. See Kren et al., Proc Natl Acad Sci USA 96:10349-10354 (1999). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild-type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.

Human Identification Applications

In addition to their diagnostic, therapeutic, and preventive uses in CVD and related pathologies, the SNPs provided by the present invention are also useful as human identification markers for such applications as forensics, paternity testing, and biometrics. See, e.g., Gill, “An assessment of the utility of single nucleotide polymorphisms (SNPs) for forensic purposes,” Int J Legal Med 114(4-5):204-10 (2001). Genetic variations in the nucleic acid sequences between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Determination of which nucleotides occupy a set of SNP positions in an individual identifies a set of SNP markers that distinguishes the individual. The more SNP positions that are analyzed, the lower the probability that the set of SNPs in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked (i.e., inherited independently). Thus, preferred sets of SNPs can be selected from among the SNPs disclosed herein, which may include SNPs on different chromosomes, SNPs on different chromosome arms, and/or SNPs that are dispersed over substantial distances along the same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use in certain forensic/human identification applications include SNPs located at degenerate codon positions (i.e., the third position in certain codons which can be one of two or more alternative nucleotides and still encode the same amino acid), since these SNPs do not affect the encoded protein. SNPs that do not affect the encoded protein are expected to be under less selective pressure and are therefore expected to be more polymorphic in a population, which is typically an advantage for forensic/human identification applications. However, for certain forensics/human identification applications, such as predicting phenotypic characteristics (e.g., inferring ancestry or inferring one or more physical characteristics of an individual) from a DNA sample, it may be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1 and 2 (which are identified as “Applera” SNP source), Tables 1 and 2 provide SNP allele frequencies obtained by re-sequencing the DNA of chromosomes from 39 individuals (Tables 1 and 2 also provide allele frequency information for “Celera” source SNPs and, where available, public SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies provided in Tables 1 and 2 enable these SNPs to be readily used for human identification applications. Although any SNP disclosed in Table 1 and/or Table 2 could be used for human identification, the closer that the frequency of the minor allele at a particular SNP site is to 50%, the greater the ability of that SNP to discriminate between different individuals in a population since it becomes increasingly likely that two randomly selected individuals would have different alleles at that SNP site. Using the SNP allele frequencies provided in Tables 1 and 2, one of ordinary skill in the art could readily select a subset of SNPs for which the frequency of the minor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables 1 and 2 provide allele frequencies based on the re-sequencing of the chromosomes from 39 individuals, a subset of SNPs could readily be selected for human identification in which the total allele count of the minor allele at a particular SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other number in-between.

Furthermore, Tables 1 and 2 also provide population group (interchangeably referred to herein as ethnic or racial groups) information coupled with the extensive allele frequency information. For example, the group of 39 individuals whose DNA was re-sequenced was made-up of 20 Caucasians and 19 African-Americans. This population group information enables further refinement of SNP selection for human identification. For example, preferred SNPs for human identification can be selected from Tables 1 and 2 that have similar allele frequencies in both the Caucasian and African-American populations; thus, for example, SNPs can be selected that have equally high discriminatory power in both populations. Alternatively, SNPs can be selected for which there is a statistically significant difference in allele frequencies between the Caucasian and African-American populations (as an extreme example, a particular allele may be observed only in either the Caucasian or the African-American population group but not observed in the other population group); such SNPs are useful, for example, for predicting the race/ethnicity of an unknown perpetrator from a biological sample such as a hair or blood stain recovered at a crime scene. For a discussion of using SNPs to predict ancestry from a DNA sample, including statistical methods, see Frudakis et al., “A Classifier for the SNP-Based Inference of Ancestry,” Journal of Forensic Sciences 48(4):771-782 (2003).

SNPs have numerous advantages over other types of polymorphic markers, such as short tandem repeats (STRs). For example, SNPs can be easily scored and are amenable to automation, making SNPs the markers of choice for large-scale forensic databases. SNPs are found in much greater abundance throughout the genome than repeat polymorphisms. Population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. SNPs are mutationally more stable than repeat polymorphisms. SNPs are not susceptible to artifacts such as stutter bands that can hinder analysis. Stutter bands are frequently encountered when analyzing repeat polymorphisms, and are particularly troublesome when analyzing samples such as crime scene samples that may contain mixtures of DNA from multiple sources. Another significant advantage of SNP markers over STR markers is the much shorter length of nucleic acid needed to score a SNP. For example, STR markers are generally several hundred base pairs in length. A SNP, on the other hand, comprises a single nucleotide, and generally a short conserved region on either side of the SNP position for primer and/or probe binding. This makes SNPs more amenable to typing in highly degraded or aged biological samples that are frequently encountered in forensic casework in which DNA may be fragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” alleles frequently encountered when analyzing STR loci. Microvariants are deletions or insertions within a repeat unit that change the size of the amplified DNA product so that the amplified product does not migrate at the same rate as reference alleles with normal sized repeat units. When separated by size, such as by electrophoresis on a polyacrylamide gel, microvariants do not align with a reference allelic ladder of standard sized repeat units, but rather migrate between the reference alleles. The reference allelic ladder is used for precise sizing of alleles for allele classification; therefore alleles that do not align with the reference allelic ladder lead to substantial analysis problems. Furthermore, when analyzing multi-allelic repeat polymorphisms, occasionally an allele is found that consists of more or less repeat units than has been previously seen in the population, or more or less repeat alleles than are included in a reference allelic ladder. These alleles will migrate outside the size range of known alleles in a reference allelic ladder, and therefore are referred to as “off-ladder” alleles. In extreme cases, the allele may contain so few or so many repeats that it migrates well out of the range of the reference allelic ladder. In this situation, the allele may not even be observed, or, with multiplex analysis, it may migrate within or close to the size range for another locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder alleles encountered in STR analysis. Importantly, microvariants and off-ladder alleles may provide significant problems, and may be completely missed, when using analysis methods such as oligonucleotide hybridization arrays, which utilize oligonucleotide probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed, may lead to improper statistical analysis, since their frequencies in the population are generally unknown or poorly characterized, and therefore the statistical significance of a matching genotype may be questionable. All these advantages of SNP analysis are considerable in light of the consequences of most DNA identification cases, which may lead to life imprisonment for an individual, or re-association of remains to the family of a deceased individual.

DNA can be isolated from biological samples such as blood, bone, hair, saliva, or semen, and compared with the DNA from a reference source at particular SNP positions. Multiple SNP markers can be assayed simultaneously in order to increase the power of discrimination and the statistical significance of a matching genotype. For example, oligonucleotide arrays can be used to genotype a large number of SNPs simultaneously. The SNPs provided by the present invention can be assayed in combination with other polymorphic genetic markers, such as other SNPs known in the art or STRs, in order to identify an individual or to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotyped for inclusion in a database of DNA genotypes, for example, a criminal DNA databank such as the FBI's Combined DNA Index System (CODIS) database. A genotype obtained from a biological sample of unknown source can then be queried against the database to find a matching genotype, with the SNPs of the present invention providing nucleotide positions at which to compare the known and unknown DNA sequences for identity. Accordingly, the present invention provides a database comprising novel SNPs or SNP alleles of the present invention (e.g., the database can comprise information indicating which alleles are possessed by individual members of a population at one or more novel SNP sites of the present invention), such as for use in forensics, biometrics, or other human identification applications. Such a database typically comprises a computer-based system in which the SNPs or SNP alleles of the present invention are recorded on a computer readable medium.

The SNPs of the present invention can also be assayed for use in paternity testing. The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in the putative father and the child, with the SNPs of the present invention providing nucleotide positions at which to compare the putative father's and child's DNA sequences for identity. If the set of polymorphisms in the child attributable to the father does not match the set of polymorphisms of the putative father, it can be concluded, barring experimental error, that the putative father is not the father of the child. If the set of polymorphisms in the child attributable to the father match the set of polymorphisms of the putative father, a statistical calculation can be performed to determine the probability of coincidental match, and a conclusion drawn as to the likelihood that the putative father is the true biological father of the child.

In addition to paternity testing, SNPs are also useful for other types of kinship testing, such as for verifying familial relationships for immigration purposes, or for cases in which an individual alleges to be related to a deceased individual in order to claim an inheritance from the deceased individual, etc. For further information regarding the utility of SNPs for paternity testing and other types of kinship testing, including methods for statistical analysis, see Krawczak, “Informativity assessment for biallelic single nucleotide polymorphisms,” Electrophoresis 20(8):1676-81 (June 1999).

The use of the SNPs of the present invention for human identification further extends to various authentication systems, commonly referred to as biometric systems, which typically convert physical characteristics of humans (or other organisms) into digital data. Biometric systems include various technological devices that measure such unique anatomical or physiological characteristics as finger, thumb, or palm prints; hand geometry; vein patterning on the back of the hand; blood vessel patterning of the retina and color and texture of the iris; facial characteristics; voice patterns; signature and typing dynamics; and DNA. Such physiological measurements can be used to verify identity and, for example, restrict or allow access based on the identification. Examples of applications for biometrics include physical area security, computer and network security, aircraft passenger check-in and boarding, financial transactions, medical records access, government benefit distribution, voting, law enforcement, passports, visas and immigration, prisons, various military applications, and for restricting access to expensive or dangerous items, such as automobiles or guns. See, for example, O'Connor, Stanford Technology Law Review, and U.S. Pat. No. 6,119,096.

Groups of SNPs, particularly the SNPs provided by the present invention, can be typed to uniquely identify an individual for biometric applications such as those described above. Such SNP typing can readily be accomplished using, for example, DNA chips/arrays. Preferably, a minimally invasive means for obtaining a DNA sample is utilized. For example, PCR amplification enables sufficient quantities of DNA for analysis to be obtained from buccal swabs or fingerprints, which contain DNA-containing skin cells and oils that are naturally transferred during contact.

Further information regarding techniques for using SNPs in forensic/human identification applications can be found, for example, in Current Protocols in Human Genetics 14.1-14.7, John Wiley & Sons, N.Y. (2002).

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art-known (i.e., wild-type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are referred to as SEQ ID NOS:308-614 in Table 1 and provided in the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic proteins/peptides/polypeptides of the present invention. The terms “protein,” “peptide,” and “polypeptide” are used herein interchangeably.

A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains.

As used herein, a protein or peptide is said to be “isolated” or “purified” when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.

As used herein, “substantially free of cellular material” includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.

The language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons that contain a SNP of the present invention.

Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.

The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.

The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.

The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein. “Operatively linked” indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence. See Ausubel et al., Current Protocols in Molecular Biology (1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.

In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, “Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems,” Appl Microbiol Biotechnol 60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al., “Designing proteins that work using recombinant technologies,” Curr Pharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al., “Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16 (October 1997).

In certain embodiments, novel compositions of the present invention also relate to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., allelic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, an aspect of the present invention that is specifically contemplated are polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1, but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Be; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found, for example, in Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.

Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis, particularly using the amino acid sequence and polymorphism information provided in Table 1. Cunningham et al., Science 244:1081-1085 (1989). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling. Smith et al., J Mol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Particularly common modifications, for example glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, are described in most basic texts, such as Proteins—Structure and Molecular Properties 2nd Ed., T. E. Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold, Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson, ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol 182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g., substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g., a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g., act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g., active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis). Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art. See, e.g., Molecular Cloning: A Laboratory Manual, Sambrook and Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology: Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel, eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS:308-614. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non-synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other.

In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing CVD or for determining predisposition to CVD in a human, for treating and/or preventing CVD, or for predicting an individual's response to a treatment (particularly treatment or prevention of CVD), etc. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as “protein chips”). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications.

One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

In vitro methods for detection of the variant proteins associated with CVD that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15; 71(12):294R-304R (June 1999).

Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g., small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g., small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.

The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non-variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab′)₂, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.

The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.

Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.

The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein. Hodgson, Bio/technology, 10(9), 973-80 (September 1992).

To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be bound to a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., ³⁵S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as CVD. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.

The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as “bait proteins” in a two-hybrid assay or three-hybrid assay to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. See, e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J Biol Chem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924 (1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO 94/10300. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein-mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non-variant proteins, i.e., the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).

As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad Sci USA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), a humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544 (1989)), a bispecific antibody with two binding specificities (Segal et al., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7 (2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., J Immunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer or trimer), and a minibody.

Many methods are known in the art for generating and/or identifying antibodies to a given target antigen. Harlow, Antibodies, Cold Spring Harbor Press, N.Y. (1989). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g., a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, which immortalizes cells secreting a specific monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975). The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000); Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding. U.S. Pat. No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read-through mutation caused by a SNP). Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-10 contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,” Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancer antibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg, “Advancing role of radiolabeled antibodies in the therapy of cancer,” Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et al., “Antibody-based therapeutics in oncology,” Expert Rev Anticancer Ther 3(1):107-21 (February 2003); Cao et al., “Bispecific antibody conjugates in therapeutics,” Adv Drug Deliv Rev 55(2):171-97 (February 2003); von Mehren et al., “Monoclonal antibody therapy for cancer,” Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001; Hudson et al., “Engineered antibodies,” Nat Med 9(1):129-34 (January 2003); Brekke et al., “Therapeutic antibodies for human diseases at the dawn of the twenty-first century,” Nat Rev Drug Discov 2(1):52-62 (January 2003); Erratum in: Nat Rev Drug Discov 2(3):240 (March 2003); Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Andreakos et al., “Monoclonal antibodies in immune and inflammatory diseases,” Curr Opin Biotechnol 13(6):615-20 (December 2002); Kellermann et al., “Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics,” Curr Opin Biotechnol 13(6):593-7 (December 2002); Pini et al., “Phage display and colony filter screening for high-throughput selection of antibody libraries,” Comb Chem High Throughput Screen 5(7):503-10 (November 2002); Batra et al., “Pharmacokinetics and biodistribution of genetically engineered antibodies,” Curr Opin Biotechnol 13(6):603-8 (December 2002); and Tangri et al., “Rationally engineered proteins or antibodies with absent or reduced immunogenicity,” Curr Med Chem 9(24):2191-9 (December 2002).

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disease progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as in CVD, or during treatment. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.

Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variant protein in disease states such as in active stages of the disease or in an individual with a predisposition to a disease related to the protein's function, such as CVD, or during the course of a treatment regime. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to diagnose CVD or to predict an individual's response to a treatment or predisposition/susceptibility to CVD, as indicated by the presence of the variant protein.

Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.

Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol. Leong et al., Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term “vector” refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. See, e.g., Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g., tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.

A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, Escherichia coli, Streptomyces spp., and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila spp., animal cells such as COS and CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (S. Gottesman, Gene Expression Technology: Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari et al., EMBO J 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (B. Seed, Nature 329:840(1987)) and pMT2PC (Kaufman et al., EMBO J 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.

Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.

While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.

For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production.

Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.

Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.

Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.

Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No. 4,873,191 by Wagner et al., and in B. Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described, for example, in I. Wilmut et al., Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G_(o) phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g., a somatic cell) is isolated.

Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).

For further information regarding transgenic animals, see Houdebine, “Antibody manufacture in transgenic animals and comparisons with other systems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Petters et al., “Transgenic animals as models for human disease,” Transgenic Res 9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenic animals in understanding molecular mechanisms of toxicity,” J Pharm Pharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant protein production in transgenic animals,” Curr Opin Biotechnol 7(5):536-40 (October 1996); Houdebine, “Transgenic animal bioreactors,” Transgenic Res 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creating transgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl et al., “Artificial chromosome vectors and expression of complex proteins in transgenic animals,” Theriogenology 59(1):107-13 (January 2003).

EXAMPLES

The following examples are offered to illustrate, but not limit, the claimed invention.

Example 1: SNP rs197922 in GOSR2 is Associated with Hypertension

Overview

A missense SNP in GOSR2 (Lys67Arg, rs197922) was analyzed for association with hypertension and blood pressure. Logistic and linear regression was used to test the association of the GOSR2 SNP with hypertension and blood pressure among 3,528 blacks and 9,861 whites from the Atherosclerosis Risk in Communities (ARIC) study. Race-specific regression models of hypertension were adjusted for age and gender. Adjustments were made for anti-hypertensive medication use when testing the association with blood pressure.

The Lys67 allele of GOSR2 was associated with increased hypertension risk in whites (adjusted odds ratio=1.09, P=0.01) (in blacks, adjusted odds ratio=0.96, P=0.47). The Lys67 allele was also associated with systolic blood pressure (SBP) in both races (adjusted β=0.87, P<0.001 and adjusted β=1.05, P=0.05 for whites and blacks, respectively). This allele was also associated with SBP in white participants of the Women's Health Study (P=0.11).

See Meyer et al., Am J Hypertens. 2009 February; 22(2):163-8, incorporated herein by reference in its entirety.

Methods

Atherosclerosis Risk in Communities Study (ARIC)

Study Population

The Atherosclerosis Risk in Communities (ARIC) study is a longitudinal cohort study of atherosclerosis, cardiovascular disease, and their risk factors. The population and study methods have been described in detail elsewhere.¹² Briefly, from 1987 to 1989, 15,792 participants between the ages of 45 to 64 were sampled from four study sites in the United States: Forsyth County, N.C.; Jackson, Miss.; suburban Minneapolis, Minn.; and Washington County, Md. At baseline and in three-year intervals following the baseline visit (1990-1992, 1993-1995, and 1996-1998) participants were interviewed and underwent a brief clinical examination. The study was approved by institutional review boards from each field center and written informed consent was obtained from participants before each examination. Follow-up examinations were supplemented with annual telephone interviews.

In the current analysis, individuals from races other than white or black (n=48) or blacks from Minnesota and Washington County (n=55) were excluded due to small numbers. Those who refused to participate in genetic studies (n=44) were also excluded. Since incident CHD was the outcome used in the primary study in which GOSR2 was selected, and since results for hypertension were similar with or without exclusion for prevalent CHD, participants were excluded for prevalent CHD (n=762), missing CHD (337), or prevalent stroke (n=331), leaving 14,215 participants (10,401 whites, 3,814 blacks, 6,146 males and 8,069 females). During 196,069 person-years of follow-up (mean 13.8 years), 1,747 (12%) of the 14,215 ARIC participants in this analysis had an incident CHD event. For the present analysis of GOSR2 and hypertension, those missing information for GOSR2 genotype (n=826) were further excluded, resulting in 13,389 participants (9,861 whites, 3,528 blacks, 5,787 males and 7,602 females). At baseline, 4,416 of the 13,389 participants (33%) reported prevalent hypertension.

Measurements

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured after resting for 5 minutes in the seated position using a random-zero sphygmomanometer. Second and third readings were averaged to derive the blood pressure measures used here. Hypertension was defined as a SBP of 140 mmHg or greater, a DBP of 90 mmHg or greater, or use of blood pressure lowering medications in the past two weeks. Waist circumference was measured once at the umbilicus with an anthropometric tape. Levels of fasting triglycerides,¹³ total cholesterol,¹⁴ high density lipoprotein cholesterol (HDL),¹⁵ and glucose¹⁶ were measured in blood samples using standard methods that have been reported previously. Low density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula.¹⁷ Carotid artery (CA) intima media thickness (IMT) was measured using high-resolution B-mode ultrasound following structured protocols as described elsewhere.^(18, 19) The mean of measurements taken at six carotid artery sites were used. High IMT was defined as ≥75% tile separately for men and women. Diabetes was defined as a fasting blood glucose of 126 mg/dL or more, a non-fasting blood glucose of 200 mg/dL or more, self-reported diabetes, or use of diabetes medications in the past two weeks. Incident CHD was defined by documented MI, unstable angina, sudden coronary death, or non-elective cardiovascular surgical procedures. Incident CHD events were determined through 2003. Follow-up time for CHD events was calculated from the date of the baseline visit to the date of the first CHD event for CHD cases or until either Dec. 31, 2003 or the last date of contact for those who did not have a CHD event. Genotypes in the ARIC participants were determined by an oligonucleotide ligation procedure that combined PCR amplification of target sequences from 3 ng of genomic DNA with subsequent allele-specific oligonucleotide ligation.²⁰ The ligation products of the two alleles were separated by hybridization to product specific oligonucleotides, each coupled to spectrally distinct Luminex100 xMAP microspheres (Luminex, Austin, Tex.). The captured products were fluorescently labeled with streptavidin R-phycoerythrin (Prozyme, San Leandro, Calif.), sorted on the basis of microsphere spectrum, and detected by a Luminex100 instrument.

SNP Selection

SNPs were identified that were associated with CHD in two antecedent case control studies of MI. Briefly, 20,009 SNPs (in 9,874 Entrez or Ensembl genes) were tested in one case control study (475 cases of MI and 649 non-MI controls). The 1,548 SNPs that were associated with MI in this first study (P<0.1), were then tested in a second case-control study of MI (793 MI cases and 1,000 healthy controls). Further details of the antecedent case control studies can be found in other references.²¹⁻²³ 77 SNPs were found that were associated with MI (P<0.1) and had the same risk alleles in both studies (Table 7). The risk alleles of 72 of these 77 SNPs were then tested for their association with time to incident CHD in ARIC using Cox proportional hazards models, where the SNPs were modeled in an additive manner along with gender and age (five of the 77 SNPs were not tested in ARIC because good quality multiplex assays could not be made for them). One of the SNPs that was associated with CHD was in GOSR2 (Lys67Arg, rs197922). Complete results for the association tests between incident CHD in ARIC for 34 of the 72 SNPs are reported in Morrison et al.²³ and Bare et al.²²

Statistics

Means and standard deviations or frequencies and percents were calculated for continuous and categorical variables, respectively. Triglyceride levels were natural-log transformed for comparison of mean levels by genotype. Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated excluding participants who were using anti-hypertensive medications. Differences in means or frequencies by genotype were determined using the F-test or chi-square test as appropriate for continuous and categorical variables. In all regression models, the GOSR2 SNP was coded in an additive manner. Linear regression was used to analyze the association between the GOSR2 SNP and the continuous variables, such as SBP and DBP. Logistic regression was used to analyze the association between the GOSR2 SNP and prevalent hypertension, elevated SBP, DBP, and IMT (≥75% tile). Linear and logistic regression models were adjusted for age and gender. Regression models of SBP and DBP were additionally adjusted for use of anti-hypertensive medications. Since additive models have been shown to perform well even when the underlying inheritance model is recessive or dominant,^(24,25) and since there is no previous literature indicating an inheritance model for the GOSR2 SNP and hypertension, estimates for the additive model for GOSR2 were reported. Differences in results by gender were evaluated using the likelihood ratio test. No significant differences by gender were detected, so gender-specific results are not presented. Power to detect an association between the GOSR2 SNP and hypertension with OR of 1.1 was 79% among white participants of ARIC and 45% among black participants.

Results

GOSR2 genotype frequencies differed by race (P<0.001; whites: ArgArg 43.2%, LysArg 44.6%, LysLys 12.2%; blacks: ArgArg 48.1%, LysArg 42.4%, LysLys 9.5%) but were consistent with Hardy-Weinberg expectations for both whites (Pearson chisquare=1.57; P=0.21) and blacks (Pearson chisquare=0.08; P=0.78).

Means and percentages for the demographic and clinical variables at baseline are presented in Table 8 according to race and genotype. Mean SBP (P=0.004) and DBP (P=0.09) among those not using anti-hypertensive medications, waist circumference (P=0.05), and CA IMT (P=0.02) differed by genotype among whites (there were no differences among blacks). The GOSR2 SNP was significantly associated with SBP in both whites (β=0.87, P<0.001) and blacks (β=1.05, P=0.05) after adjustment for age, gender, and use of anti-hypertensive medications. The GOSR2 SNP was also associated with DBP among whites after adjustment (β=0.37, P=0.01) (in blacks, after adjustment, β=0.44, P=0.14). Prevalent hypertension at baseline also differed by genotype among whites (P<0.01) (among blacks, P=0.66).

The risk associated with the GOSR2 SNP and blood pressure was assessed using dichotomized SBP and DBP variables (>75% tile). An association was found between the Lys67 allele of the GOSR2 SNP and elevated SBP (OR: 1.08; 95% CI: 1.00 to 1.15) and elevated DBP (OR: 1.08; 95% CI: 1.01 to 1.16) among whites (Table 9). The risk associated with GOSR2 and a dichotomized IMT variable was also assessed and found to be associated with elevated CA IMT (OR: 1.09; 95% CI: 1.01 to 1.17) among whites. The effect sizes were similar across measures of high blood pressure and consistent with the comparison of means by genotype in Table 8. In a genotypic assessment of the GOSR2 variant associated with hypertension among whites, the OR for LysArg compared to ArgArg and LysLys compared to ArgArg were similar in magnitude (OR: 1.18; 95% CI: 1.06 to 1.30 and OR: 1.13; 95% CI: 0.97 to 1.31, respectively), consistent with a dominant inheritance model for GOSR2 and hypertension in whites.

Discussion

The GOSR2 Lys67Arg SNP (rs197922) was analyzed for association with hypertension in the ARIC study and it was found that the Lys67 allele was associated with hypertension, as well as with elevated SBP and DBP. The Lys67 allele had been shown to be associated with increased risk of CHD in antecedent studies (Table 7). In this example, the GOSR2 Lys67 allele was found to be associated with increased occurrence of hypertension in white participants in the ARIC study (additive OR: 1.09; 95% CI: 1.02 to 1.17; dominance OR: 1.16; 95% CI 1.06 to 1.28). This Lys67 allele was also found to be associated with quantitative traits such as SBP, DBP, and CA IMT among whites in ARIC. Linear regression revealed that the Lys67 allele was also associated with SBP among black participants of ARIC after adjusting for age, gender, and use of anti-hypertensive medication.

The association between the Lys67 allele of GOSR2 and blood pressure was also tested in white participants of the Women's Health Study (WHS).²⁶ Allele frequencies of Lys67Arg in the white participants of WHS were similar to those of white participants of ARIC (data not shown). An association with increased SBP was observed for the Lys67 allele of GOSR2 in this WHS population (OR=1.03; P=0.04, in an ordinal logistic regression of nine SBP categories after adjusting for age) (OR=1.03 and P=0.11 after additionally adjusting for use of anti-hypertensive medications).

GOSR2

GOSR2 codes for a vesicular N-ethylmaleimide sensitive factor attachment protein receptor (v-SNARE) that is involved in intra-Golgi trafficking of vesicles.²⁹ v-SNAREs such as GOSR2 interact with target-localized SNAREs (t-SNAREs) to allow directed movement of macromolecules, such as insulin, leptin, and angiotensinogen, between Golgi compartments.³⁰⁻³² GOSR2 is expressed in multiple tissues.⁷

GOSR2 is located under linkage peaks with hypertension on human chromosome 17,⁸⁻¹⁰ as well as the syntenic rat chromosome 10, and murine chromosome 11.¹¹ Despite the evidence in both humans and animal models for the region's contribution to blood pressure and risk of hypertension, an association between GOSR2 and hypertension has not previously been reported. Other genes in this region may be considered candidates for essential hypertension, but of these only MYL4 (myosin light polypeptide 4) is in a LD region with the GOSR2 rs197922 polymorphism. Using data from the International HapMap Project,²⁸ one SNP (rs16941671) from MYL4 was in moderate LD with GOSR2 rs197922 (r²=0.19; D′=0.87) in the CEPH (Utah residents with ancestry from northern and western Europe) population.

Since GOSR2 codes for a vesicular membrane protein involved in intra-Golgi protein trafficking, the results described here indicate that protein processing in the Golgi influences blood pressure levels and risk of hypertension, and altered regulation of protein trafficking (such as may be attributable to a SNP such as rs197922 that can cause alternative amino acids to be encoded) within the Golgi may contribute to blood pressure and essential hypertension.

REFERENCES (REFERENCE NUMBERS CORRESPONDS TO EXAMPLE 1 ONLY, WITH THE EXCEPTION OF REFERENCE NUMBERS 33 AND 34 WHICH CORRESPOND TO TABLE 7)

-   1. Kearney P M, Whelton M, Reynolds K, Muntner P, Whelton P K, He J.     Global burden of hypertension: Analysis of worldwide data. Lancet.     2005; 365:217-223. -   2. Centers for Disease Control and Prevention. National Center for     Health Statistics. FastStats. -   3. Ostchega Y, Yoon S S, Hughes J, Louis T. Hypertension awareness,     treatment and control—continued disparities in adults: United     states, 2005-2006. 2008; NCHS data brief no 3. Hyatsville, Md.:     National Center for Health Statistics. -   4. Hajjar I, Kotchen T A. Trends in prevalence, awareness,     treatment, and control of hypertension in the United States,     1988-2000. JAMA. 2003; 290:199-206. -   5. Cowley A W, Jr. The genetic dissection of essential hypertension.     Nature Reviews Genetics. 2006; 7:829-840. -   6. Binder A. A review of the genetics of essential hypertension.     Curr Opin Cardiol. 2007; 22:176-184. -   7. Lowe S L, Peter F, Subramaniam V N, Wong S H, Hong W. A SNARE     involved in protein transport through the Golgi apparatus. Nature.     1997; 389:881-884. -   8. Levy D, DeStefano A L, Larson M G, O'Donnell, C J, Lifton R P,     Gavras H, Cupples L A, Myers R H. Evidence for a gene influencing     blood pressure on chromosome 17. Genome scan linkage results for     longitudinal blood pressure phenotypes in subjects from the     Framingham heart study. Hypertension. 2000; 36:477-483. -   9. Baima J, Nicolaou M, Schwartz F, DeStefano A L, Manolis A, Gavras     I, Laffer C, Elijovich F, Farrer L, Baldwin C T, Gavras H. Evidence     for linkage between essential hypertension and a putative locus on     human chromosome 17. Hypertension. 1999; 34:4-7. -   10. Julier C, Delepine M, Keavney B, Terwilliger J, Davis S, Weeks D     E, Bui T, Jeunemaitre X, Velho G, Froguel P, Ratcliffe P, Corvol P,     Soubrier F, Lathrop G M. Genetic susceptibility for human familial     essential hypertension in a region of homology with blood pressure     linkage on rat chromosome 10. Hum Mol Genet. 1997; 6:2077-2085. -   11. Knight J, Munroe P B, Pembroke J C, Caulfield M J. Human     chromosome 17 in essential hypertension. Ann Hum Genet. 2003;     67:193-206. -   12. The Atherosclerosis Risk in Communities (ARIC) study: Design and     objectives. The ARIC investigators. Am J Epidemiol. 1989;     129:687-702. -   13. Nagele U, Hagele E O, Sauer G, Wiedemann E, Lehmann P, Wahlefeld     A W, Gruber W. Reagent for the enzymatic determination of serum     total triglycerides with improved lipolytic efficiency. Journal of     Clinical Chemistry & Clinical Biochemistry. 1984; 22:165-174. -   14. Siedel J, Hagele E O, Ziegenhorn J, Wahlefeld A W. Reagent for     the enzymatic determination of serum total cholesterol with improved     lipolytic efficiency. Clin Chem. 1983; 29:1075-1080. -   15. Warnick G R, Benderson J, Albers J J. Dextran sulfate-Mg2+     precipitation procedure for quantitation of high-density-lipoprotein     cholesterol. Clin Chem. 1982; 28:1379-1388. -   16. Operations manual no. 10: Clinical chemistry determinations,     version 1.0.; Chapel Hill: ARIC Coordinating Center, School of     Public Health, University of North Carolina. 1987. -   17. Friedewald W T, Levy R I, Fredrickson D S. Estimation of the     concentration of low-density lipoprotein cholesterol in plasma,     without use of the preparative ultracentrifuge. Clin Chem. 1972;     18:499-502. -   18. Anonymous. High-resolution B-mode ultrasound scanning methods in     the Atherosclerosis Risk in Communities study (ARIC). The ARIC study     group. Journal of Neuroimaging. 1991; 1:68-73. -   19. Stevens J, Tyroler H A, Cai J, Paton C C, Folsom A R, Tell G S,     Schreiner P J, Chambless L E. Body weight change and carotid artery     wall thickness. The Atherosclerosis Risk in Communities (ARIC)     study. Am J Epidemiol. 1998; 147:563-573. -   20. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z,     Arellano A R, Lumley T, Rice K, Iakoubova O, Luke M M, Young B A,     Malloy M J, Kane J P, Ellis S G, Tracy R P, Devlin J J, Psaty B M.     Association of gene variants with incident myocardial infarction in     the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol.     2008:28:173-179. -   21. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M,     Iakoubova O A, Pullinger C R, Cassano J, Aouizerat B E, Fenwick R G,     Reitz R E, Catanese J J, Leong D U, Zellner C, Sninsky J J, Topol E     J, Devlin J J, Kane J P. Identification of four gene variants     associated with myocardial infarction. Am J Hum Genet. 2005;     77:596-605. -   22. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M,     Iakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S,     Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants     identify elevated genetic risk for coronary heart disease. Genetics     in Medicine. 2007; 9:682-689. -   23. Morrison A C, Bare L A, Chambless L E, Ellis S G, Malloy M, Kane     J P, Pankow J S, Devlin J J, Willerson J T, Boerwinkle E. Prediction     of coronary heart disease risk using a genetic risk score: The     Atherosclerosis Risk in Communities study. Am J Epidemiol. 2007;     166:28-35. -   24. Horvath S, Xu X, Laird N M. The family based association test     method: Strategies for studying general genotype—phenotype     associations. European Journal of Human Genetics. 2001; 9:301-306. -   25. Balding D J. A tutorial on statistical methods for population     association studies. Nature Reviews Genetics. 2006; 7:781-791. -   26. Rexrode K M, Lee I M, Cook N R, Hennekens C H, Buring J E.     Baseline characteristics of participants in the Women's Health     Study. Journal of Womens Health & Gender-Based Medicine. 2000;     9:19-27. -   27. Bui T D, Levy E R, Subramaniam V N, Lowe S L, Hong W. cDNA     characterization and chromosomal mapping of human golgi SNARE GS27     and GS28 to chromosome 17. Genomics. 1999; 57:285-288. -   28. The International HapMap Consortium. The International HapMap     Project. Nature. 2003; 426:789-796. -   29. Hay J C, Klumperman J, Oorschot V, Steegmaier M, Kuo C S,     Scheller R H. Localization, dynamics, and protein interactions     reveal distinct roles for ER and golgi SNAREs. J Cell Biol. 1998;     141:1489-1502. -   30. Sollner T, Bennett M K, Whiteheart S W, Scheller R H, Rothman     J E. A protein assembly-disassembly pathway in vitro that may     correspond to sequential steps of synaptic vesicle docking,     activation, and fusion. Cell. 1993; 75:409-418. -   31. Sollner T, Whiteheart S W, Brunner M, Erdjument-Bromage H,     Geromanos S, Tempst P, Rothman J E. SNAP receptors implicated in     vesicle targeting and fusion. Nature. 1993; 362:318-324. -   32. Rothman J E. Mechanisms of intracellular protein transport.     Nature. 1994; 372:55-63. -   33. Morrison A C, Bare L A, Chambless L E, Ellis S G, Malloy M, Kane     J P, Pankow J S, Devlin J J, Willerson J T, Boerwinkle E. Prediction     of coronary heart disease risk using a genetic risk score: The     Atherosclerosis Risk in Communities study. Am J Epidemiol. 2007;     166:28-35. -   34. Bare L A, Morrison A C, Rowland C M, Shiffman D, Luke M M,     Iakoubova O A, Kane J P, Malloy M J, Ellis S G, Pankow J S,     Willerson J T, Devlin J J, Boerwinkle E. Five common gene variants     identify elevated genetic risk for coronary heart disease. Genetics     in Medicine. 2007; 9:682-689.

Example 2: Identification of Five SNPs in Four Genes that are Associated with Myocardial Infarction

Overview

17,576 SNPs that could affect gene function or expression were analyzed for association with MI. The testing of these SNPs was staged in three case-control studies of MI. In the first study (762 cases, 857 controls), 17,576 SNPs were tested and 1,949 SNPs were found that were associated with MI (P<0.05). These 1,949 SNPs were tested in a second study (579 cases and 1159 controls) and it was found that 24 of these SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, these 24 SNPs were tested in a third study (475 cases and 619 controls) and it was found that 5 of these SNPs, which are located in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA), were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies.

Thus, 5 SNPs were identified that are associated with MI.

See Shiffman et al., PLoS ONE. 2008 Aug. 6; 3(8):e2895, incorporated herein by reference in its entirety.

Methods

Objectives

To identify genetic polymorphisms associated with MI, three case-control studies comprising cases with a history of MI and controls without a history of MI were interrogated. The first two case-control studies (Study 1 and Study 2) identified SNPs associated with MI. The hypotheses that these SNPs are associated with MI were tested in Study 3. The allele frequency of each SNP was determined in pools of case and control DNA prior to determining the genotype of a smaller number of SNPs for all individual DNA samples.

Participants

Participants in Study 1 and Study 2 were enrolled between July 1989 and May 2005 by the University of California, San Francisco (UCSF) Genomic Resource in Arteriosclerosis. UCSF samples received at the Celera genotyping facility by May 2004 were considered for inclusion in Study 1. Samples that arrived past that date were considered for Study 2. Cases in Study 1 and Study 2 included patients who had undergone diagnostic or interventional cardiac catheterization and patients of the UCSF Lipid Clinic. Controls were enrolled by the UCSF Genomic Resource in Arteriosclerosis and included UCSF staff, patients of UCSF Clinics, and senior citizens who participated in physical activities at regional community centers and events for senior citizens. A history of MI for Study 1 cases was verified by a clinical chart review or by The International Classification of Diseases, 9^(th) Revision (ICD9) codes 410 or 411 in the patient records. MI status for Study 2 cases was determined by ICD9 codes 410 or 411 or by a self-reported history of MI. To characterize the accuracy of these self-reported histories, medical record review for a sample of Study 2 cases resulted in verification of the self-reported MI status for 98% of the sample (verification by electrocardiogram, cardiac enzymes or imaging). Controls had no history of MI, diabetes or symptomatic vascular disease. All participants of Study 1 and Study 2 chose Caucasian as their ethnicity in response to a multiple-choice questionnaire.

Participants in Study 3 were patients of the Cleveland Clinic Foundation (CCF) Heart Center who had undergone diagnostic or interventional cardiac catheterization between July 2001 and March 2003 and enrolled in the Genebank at Cleveland Clinic Study. A history of MI was verified by electrocardiogram, cardiac enzymes, or perfusion imaging. Controls had less than 50% coronary luminal narrowing. All participants in Study-3 selected North European, Eastern European, or ‘other Caucasian’ as the description of both their mother and father on the enrollment questionnaire. The demographic and risk factor characteristics of the participants in the 3 studies are presented in Table 11.

SNP Selection

The 17,576 SNPs investigated in Study 1 are located in 10,152 genes. These SNPs could potentially affect gene function or expression. Most (65%) of these SNPs were missense, nonsense, or were located in acceptor and donor splice sites. Other SNPs were located in transcription factor binding sites, microRNA binding sites, exon splice enhancer and silencer sites, or in untranslated regions of mRNA.

Allele Frequency and Genotype Determination

DNA concentrations were standardized to 10 ng/μL using PicoGreen (Molecular Probes) fluorescent dye. DNA pools, typically of 50 cases or controls, were made by mixing equal volumes of standardized DNA from each individual member of the pool. Each allele was amplified separately by PCR using 3 ng of pooled DNA. The allele frequency was calculated from amplification curves for each allele. At least four independent pools of DNA were amplified in duplicate for each allele. Genotyping of individual DNA samples was similarly performed using 0.3 ng of DNA.

Ethics

Subjects of all three studies gave informed consent and completed an Institutional Review Board approved questionnaire.

Statistical Methods

Association between MI status and allele frequencies was assessed by two-tailed χ² tests, and between MI status and genotype by logistic regression using an additive inheritance model (Wald test). In Study 2 and Study 3, since a single prespecified risk allele was tested for each SNP, one-sided P values and 90% confidence intervals are presented (for odds ratios greater than one, there is 95% confidence that the true risk estimate is greater than the lower bound of a 90% confidence interval). A P threshold value of 0.05 was used in all three studies, and adjusted for multiple testing by calculating the false discovery rate (FDR) in Study 3. FDR was calculated using the MULTTEST procedure (SAS statistical package Version 9.1); for SNPs that were in the same gene, only the SNP with the higher (less significant) P value was included in the calculation.

Results

The allele frequencies of 17,576 putative functional SNPs were measured in Study 1 cases and controls using pooled DNA samples, and 1,949 SNPs were identified that were associated with MI (P<0.05) and had minor allele frequency estimates that were greater than 1%. For these 1,949 SNPs, allele frequencies in Study 2 cases and controls were determined using pooled DNA samples and it was verified that the risk allele identified in Study 1 was also associated with risk of MI in Study 2. For those SNPs that were associated with MI and had the same risk alleles in both pooling studies, the association of the SNP with MI in Study 1 and Study 2 was then confirmed by genotyping individual DNA samples. It was found that the risk alleles of 24 SNPs in 23 genes were associated with MI in both studies using an additive inheritance model (Table 12) and a P value threshold of 0.05. Next, the hypotheses that the risk alleles of these 24 SNPs would be associated with MI were tested in Study 3. It was found that the risk allele of 5 SNPs, in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI using an additive inheritance model after adjustment for age and sex (Table 13) (false discovery rate=0.23). The distribution of the genotypes for each of the SNPs did not deviate from what was expected under Hardy-Weinberg equilibrium (P>0.5). Further adjustment for traditional risk factors (dyslipidemia, hypertension, smoking status, and BMI), did not appreciably change the risk estimate for the four SNPs LPA, FXN (2 SNPs), and HLA-DPB2 (Table 13; for the ENO1 SNP, after further adjustment for traditional risk factors, OR=1.09, 90% CI 0.85-1.38, P=0.28, and the ENO1 SNP trended toward association with dyslipidemia (P=0.1)).

Discussion

An analysis was conducted of 17,576 SNPs that could potentially affect gene function or expression in three case-control studies of MI, and 5 SNPs were identified in four genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) that were associated with MI.

The first SNP is located in ENO1, a gene that encodes α-enolase, a glycolytic enzyme that catalyzes the conversion of 2-phospho-D-glycerate to phosphoenolpyruvate. α-enolase is also known to be a plasminogen receptor on the surface of hematopoietic cells and endothelial cells [11]. Thus, α-enolase could contribute to fibrinolysis, hemostasis, and arterial thrombus formation—processes that are critical in the pathophysiology of MI. The SNP in ENO1 (rs1325920) is located about 1 kb upstream of the gene and could be involved in transcriptional regulation.

Two of the SNPs are in the FXN gene. The FXN gene encodes Frataxin, a mitochondrial protein involved in maintaining cellular iron homeostasis [12]. Expanded GAA triplet repeats in intron 1 of FXN leads to silencing of the FXN gene and to accumulation of iron in the mitochondria, which makes mitochondria sensitive to oxidative stress [13]. These changes lead to Friedreich's ataxia, an autosomal recessive disease of the central nervous system that is frequently associated hypertrophic cardiomyopathy [12]. The two SNPs in FXN found to be associated with MI are located in the 3′ untranslated region of F×N (rs10890) and in a putative transcription factor binding site (rs3793456), thus one or both of these SNPs could have an effect on FXN gene expression. These two SNPs are in linkage disequilibrium (r²=0.57 in Study 1).

The fourth SNP (rs3798220 in LPA) encodes a methionine to isoleucine substitution at amino acid 4399 of apolipoprotein(a). It has been previously shown that this SNP is associated with coronary artery narrowing and with increased levels of plasma lipoprotein(a) in case-control studies [10]. This SNP was also associated with incident myocardial infarction in the Cardiovascular Health Study, a population-based prospective study of about 5000 individuals aged 65 or older [14].

As described above, certain aspects of the invention relate to using SNP rs3798220 for utilities related to hormone replacement therapy (HRT).

The fifth SNP that is associated with MI in this study is in HLA-DPB2 (rs35410698). HLA-DPB2 is a pseudogene in the Human Leukocyte Antigen (HLA) region [15].

REFERENCES (REFERENCE NUMBERS CORRESPOND TO EXAMPLE 2 ONLY)

-   1 American Heart Association (2002) Heart disease and stroke     statistics: 2005 update. American Heart Association, Dallas -   2. Marenberg M E, Risch N, Berkman L F, Floderus B, de Faire     U (1994) Genetic susceptibility to death from coronary heart disease     in a study of twins. N Engl J Med 330:1041-1046 -   3. Cohen J C, Boerwinkle E, Mosley T H Jr, Hobbs H H (2006) Sequence     variations in PCSK9, low LDL, and protection against coronary heart     disease. N Engl J Med 354:1264-1272. -   4. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt N P et     al. (2008) Polymorphisms associated with cholesterol and risk of     cardiovascular events. N Engl J Med 358:1240-1249. -   5. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R et     al. (2007) A common allele on chromosome 9 associated with coronary     heart disease. Science 316:1488-1491. -   6. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S,     Blondal T et al. (2007) A common variant on chromosome 9p21 affects     the risk of myocardial infarction. Science 316:1491-1493. -   7. Shiffman D, Rowland C M, Sninsky J J, Devlin J J (2006)     Polymorphisms associated with coronary heart disease: better by the     score. Curr Opin Mol Ther 8:493-499. -   8. Shiffman D, Ellis S G, Rowland C M, Malloy M J, Luke M M et     al. (2005) Identification of four gene variants associated with     myocardial infarction. Am J Hum Genet 77:596-605. -   9. Shiffman D, Rowland C M, Louie J Z, Luke M M, Bare L A et     al. (2006) Gene Variants of VAMP8 and HNRPUL1 Are Associated With     Early-Onset Myocardial Infarction. Arterioscler Thromb Vasc Biol     26:1613-1618. -   10. Luke M M, Kane J P, Liu D M, Rowland C M, Shiffman D et     al. (2007) A polymorphism in the protease-like domain of     apolipoprotein(a) is associated with severe coronary artery disease.     Arterioscler Thromb Vasc Biol 27:2030-2036. -   11. Pancholi V. (2001) Multifunctional alpha-enolase: its role in     diseases. Cell Mol Life Sci 58:902-920. -   12. Gottesfeld J M (2007) Small molecules affecting transcription in     Friedreich ataxia. Pharmacol Ther 116:236-248. -   13. Al-Mandawi S, Pinto R M, Varshney D, Lawrence L, Lowrie M B et     al. (2006) Genomics 88:580-590. -   14. Shiffman D, O'Meara E S, Bare L A, Rowland C M, Louie J Z et     al. (2008) Association of Gene Variants With Incident Myocardial     Infarction in the Cardiovascular Health Study. Arterioscler Thromb     Vasc Biol 28:173-179. -   15. de Bakker P I, McVean G, Sabeti P C, Miretti M M, Green T et     al. (2006) A high-resolution HLA and SNP haplotype map for disease     association studies in the extended human MHC. Nat Genet     38:1166-1172. -   16. Topol E J, McCarthy J, Gabriel S, Moliterno D J, Rogers W J et     al. (2001) Single nucleotide polymorphisms in multiple novel     thrombospondin genes may be associated with familial premature     myocardial infarction. Circulation 104:2641-2644.

Example 3: Fine-Mapping SNPs Associated with CVD

SNPs Surrounding GOSR2 SNP Rs197922 (hCV2275273)

As described above in Example 1, a SNP in GOSR2 (rs197922, hCV2275273) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 17 surrounding this GOSR2 SNP, other SNPs in a 215 kb region surrounding rs197922 were genotyped and analyzed. This region of 215 kb included all the SNPs with r²>0.3 with rs197922 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF Study 1 (“UCSF1”) (793 MI cases and 1000 controls). For SNPs that were in LD with rs197922 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 10.

SNPs Surrounding ENO1 SNP Rs1325920 (hCV8824241)

As described above in Example 2, a SNP in ENO1 (rs1325920, hCV8824241) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 1 surrounding this ENO1 SNP, other SNPs in a 582 kb region surrounding rs1325920 were genotyped and analyzed. This region of 582 kb included all the SNPs with r²>0.3 with rs1325920 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs1325920 (r²>0.3), tagging SNPs with r²>0.90 were used. Some of the SNPs that were associated with MI in UCSF1 were also genotyped in a second sample set, UCSF2 (579 MI cases and 1159 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 and were also associated with MI in UCSF2 (or were not tested in UCSF2) are provided in Table 14.

SNPs Surrounding FXN SNP Rs10890 (hCV1463226)

As described above in Example 2, a SNP in FXN (rs10890, hCV1463226) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 9 surrounding this FXN SNP, other SNPs in a 203 kb region surrounding rs10890 were genotyped and analyzed. This region of 203 kb included all the SNPs with r²>0.3 with rs10890 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs10890 (r²>0.3), tagging SNPs with r²>0.90 were used. Some of the SNPs that were associated with MI in UCSF1 were also genotyped in a second sample set, UCSF2 (579 MI cases and 1159 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 and were also associated with MI in UCSF2 (or were not tested in UCSF2) are provided in Table 15.

SNPs Surrounding RERE SNP Rs10779705 (hCV32055477)

As shown in Table 14 (SNPs surrounding ENO1), a SNP in RERE (rs10779705, hCV32055477) was been identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 1 surrounding this RERE SNP, other SNPs in a 596 kb region surrounding rs10779705 were genotyped and analyzed. This region of 596 kb included all the SNPs with r²>0.3 with rs10779705 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). For SNPs that were in LD with rs10779705 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 16.

SNPs Surrounding VAMP8 SNP Rs1010 (hCV2091644)

A SNP in VAMP8 (rs1010, hCV2091644) has been identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 2 surrounding this VAMP8 SNP, other SNPs in a 220 kb region surrounding rs1010 were genotyped and analyzed. This region of 220 kb included all the SNPs with r²>0.3 with rs1010 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (793 MI cases and 1000 controls). For SNPs that were in LD with rs1010 (r²>0.3), tagging SNPs with r²>0.90 were used. SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 17.

SNPs Surrounding LPA SNP Rs3798220 (hCV25930271)

As described above in Example 2, a SNP in LPA (rs3798220, hCV25930271) was identified as being associated with MI. In order to determine if there are other SNPs that are also associated with MI in the region of chromosome 6 surrounding this LPA SNP, other SNPs in a 442 kb region surrounding rs3798220 (between rs9355797 and rs1950562) were genotyped and analyzed. This region of 442 kb included all the SNPs with r²>0.2 with rs3798220 based on Hapmap Caucasian population. SNPs in this region were interrogated using tagging SNPs. SNPs which tagged other SNPs in this region with r²>0.8 were genotyped in samples from UCSF1 (762 MI cases and 857 controls). SNPs that were significantly associated with MI (1-sided p-value of <0.05) in UCSF1 are provided in Table 18.

In a further analysis of SNPs in this 442 kb region surrounding rs3798220, SNPs were analyzed for association with MI risk using a meta-analysis of two case-control studies of MI, the UCSF1 and USCF2 studies. As indicated in the preceding paragraph, the UCSF1 study included 762 MI cases and 857 controls. The UCSF2 study included 579 MI cases and 1159 controls. In both the UCSF1 and UCSF2 studies, cases had a confirmed history of MI and controls had no history of CHD. A meta-analysis of the UCSF1 and UCSF2 studies was also used to analyze whether these SNPs are also associated with Lp(a) levels (Lpa level was transformed to Log 10Lpa). SNPs that were significantly associated (p-value of <0.1) with both MI risk and Lp(a) levels in the meta-analysis of the UCSF1 and UCSF2 studies are provided in Table 19.

Example 4: SNPs (from a Functional Genome Scan) Associated with CVD in Two Studies

SNPs identified in a functional genome scan (FGS) were analyzed for their association with CVD, particularly MI. For these SNPs, genetic data from two case-control studies of MI were analyzed without stratification. In one study, UCSF1, there were 762 cases and 857 controls. In the second study, UCSF2, there were 579 cases and 1159 controls. In both studies, cases had a confirmed history of MI and controls had no history of CHD. SNPs showing significant (p-value of <0.1) association with MI risk in both studies are provided in Table 20.

Example 5: SNPs Associated with Response to Statin Therapy and with Risk for CVD in the CARE Study

The CARE (“Cholesterol and Recurrent Events”) study, which is a randomized multicentral double-blinded trial of secondary prevention of MI with pravastatin (Pravachol®) in individuals who have previously had an MI, is described in Sacks et al. (1991) Am. J. Cardiol. 68: 1436-1446 and Sacks et al. (1996) New England Journal of Medicine 335: 1001-1009. The CARE trial, including an analysis of SNPs therein, is also described in lakoubova et al., “Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials”, J Am Coll Cardiol. 2008 Jan. 29; 51(4):435-43.

A well-documented MI was one of the enrollment criteria for entry into the CARE study. Patients were enrolled in the CARE trial from 80 participating study centers. Men and post-menopausal women were eligible for the trial if they had had an acute MI between 3 and 20 months prior to randomization, were 21 to 75 years of age, and had plasma total cholesterol levels of less than 240 mg/deciliter, LDL cholesterol levels of 115 to 174 mg/deciliter, fasting triglyceride levels of less than 350 mg/deciliter, fasting glucose levels of no more than 220 mg/deciliter, left ventricular ejection fractions of no less than 25%, and no symptomatic congestive heart failure. Patients were randomized to receive either 40 mg of pravastatin once daily or a matching placebo. The primary endpoint of the CARE trial was death from a coronary event or nonfatal MI and the median duration of follow-up was 5.0 years (range, 4.0 to 6.2 years). For the study of CARE described in this Example and shown in Tables 21-22, two endpoints were investigated: the primary endpoint of CARE (a composite endpoint of fatal coronary event or nonfatal MI, and identified as “endpt1” in the Endpoint column of Tables 21-22) and a composite endpoint of confirmed fatal or nonfatal MI (identified as “rmi” in the Endpoint column of Tables 21-22).

Table 21 provides SNPs associated with reduction of CHD risk, particularly risk for MI and recurrent MI, by Pravastatin in the CARE study, and Table 22 provides SNPs associated with risk of CHD, particularly risk for MI and recurrent MI, in the placebo arm of the CARE study. The SNPs provided in Table 22 are a subset of the SNPs provided in Table 21; thus, the SNPs provided in Table 22 are associated with both increased CHD risk as well as reduction of CHD risk by statin treatment (e.g., Pravastatin).

Specifically, Table 21 provides SNPs for which the effect of pravastatin on the primary endpoint of the CARE study (identified as “endpt1” in the Endpoint column) or the recurrent MI endpoint (identified as “rmi” in the Endpoint column) was analyzed by genotype subgroups and for which pravastatin reduced risk in one genotype subgroup but not in another (P-interaction between statin treatment and genotype for the enpdpoint <0.1).

Table 22 provides a subset of SNPs from Table 21 that were associated (p<0.1) with time to occurrence of first event, either the CARE primary endpoint (“endpt1”) or recurrent MI endpoint (“rmi”), in the placebo group of the CARE study. In Table 22, the HR (including lower and upper confidence intervals) and p-values indicated for each SNP correspond to Allele 1 (Allele 2 is the reference allele, which is considered to have HR=1).

HR stands for Hazard Ratio, which is a concept similar to Odds Ratio (OR). The HR in event-free survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For examples, HR describes the likelihood of developing MI based on comparison of rate of coronary events between carriers of a certain allele and noncarriers of the allele; therefore, HR=1.5 would mean that carriers of the allele have 50% higher risk of coronary events during the study follow-up than non-carriers. HR can also describe the effect of statin therapy on coronary events based on comparison of the rate of coronary events between patients treated with statin and patients treated with placebo in subgroups defined by SNP genotype; therefore, HR=0.5 would mean that, for example, carriers of a certain allele had a 50% reduction of coronary events by statin therapy as compared to placebo. In Table 21, p-interaction values were calculated. An interaction (or effect modification) is formed when a third variable modifies the relation between an exposure and outcome. A p-interaction <0.1 indicates that a third variable (genotype) modifies the relation between an exposure (statin treatment) and outcome (CARE primary endpoint or recurrent MI). Genotype and drug interaction is present when the effect of statins (incidence rate of disease in statin-treated group, as compared to placebo) differs in patients with different genotypes.

Example 6: Calculated Linkage Disequilibrium (LD) SNPs Associated with CVD

Another investigation was conducted to identify additional SNPs that are calculated to be in linkage disequilibrium (LD) with certain “interrogated SNPs” that have been found to be associated with CVD (particularly CHD, especially MI, or hypertension), as described herein and shown in the tables. The interrogated SNPs are shown in column 1 (which indicates the hCV identification numbers of each interrogated SNP) and column 2 (which indicates the public rs identification numbers of each interrogated SNP) of Table 6. The methodology is described earlier in the instant application. To summarize briefly, the power threshold (T) was set at an appropriate level, such as 51%, for detecting disease association using LD markers. This power threshold is based on equation (31) above, which incorporates allele frequency data from previous disease association studies, the predicted error rate for not detecting truly disease-associated markers, and a significance level of 0.05. Using this power calculation and the sample size, a threshold level of LD, or r² value, was derived for each interrogated SNP (r_(T) ², equations (32) and (33) above). The threshold value r_(T) ² is the minimum value of linkage disequilibrium between the interrogated SNP and its LD SNPs possible such that the non-interrogated SNP still retains a power greater or equal to T for detecting disease association.

Based on the above methodology, LD SNPs were found for the interrogated SNPs. Several exemplary LD SNPs for the interrogated SNPs are listed in Table 6; each LD SNP is associated with its respective interrogated SNP. Also shown are the public SNP IDs (rs numbers) for the interrogated and LD SNPs, when available, and the threshold r² value and the power used to determine this, and the r² value of linkage disequilibrium between the interrogated SNP and its corresponding LD SNP. As an example in Table 6, the interrogated SNP rs2145270 (hCV10048483) was calculated to be in LD with rs1000972 (hCV10048484) at an r² value of 0.9242, based on a 51% power calculation, thus establishing the latter SNP as a marker associated with CVD as well.

In general, the threshold r_(T) ² value can be set such that one of ordinary skill in the art would consider that any two SNPs having an r² value greater than or equal to the threshold r_(T) ² value would be in sufficient LD with each other such that either SNP is useful for the same utilities, such as determining an individual's risk for CVD such as CHD (particularly MI) or hypertension. For example, in various embodiments, the threshold r_(T) ² value used to classify SNPs as being in sufficient LD with an interrogated SNP (such that these LD SNPs can be used for the same utilities as the interrogated SNP, for example) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r² value in-between these values). Threshold r_(T) ² values may be utilized with or without considering power or other calculations.

All publications and patents cited in this specification are herein incorporated by reference in their entirety. Modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims.

TABLE 5 Primer 1 (Allele- Primer 2 (Allele- Marker Alleles Specific Primer) Specific Primer) Common Primer hCV10048483 C/T ACAGCGTTTGACACTTC AACAGCGTTTGACACTT GAAACTAGGAGCAGAGG G CA AGAGACTA (SEQ ID NO: 4007) (SEQ ID NO: 4008) (SEQ ID NO: 4009) hCV1026586 A/G GTCCAGCTTAATAATTA TCCAGCTTAATAATTAA GCCATGAGCTCATTGCC ACTTGTCAAATT CTTGTCAAATC TACAA (SEQ ID NO: 4010) (SEQ ID NO: 4011) (SEQ ID NO: 4012) hCV1030264 A/G AGGTAGATATCGTGGCT GGTAGATATCGTGGCTA CGTCTTCTCGGATGTCA AAGAT AGAC TAGTGC (SEQ ID NO: 4013) (SEQ ID NO: 4014) (SEQ ID NO: 4015) hCV1116794 A/G GTGAGTTCTCAGATGGT TGAGTTCTCAGATGGTT GCTTCAAGCTGTTGACA TGA GG GTG (SEQ ID NO: 4016) (SEQ ID NO: 4017) (SEQ ID NO: 4018) hCV11170747 A/G AATTTTTCATTCTGCAT AATTTTTCATTCTGCAT CCAGGGCTCTTTCAAGA GTGTT GTGTC TAGTA (SEQ ID NO: 4019) (SEQ ID NO: 4020) (SEQ ID NO: 4021) hCV11181829 C/T GATGGAGTTTTGAGGAA CGATGGAGTTTTGAGGA CCCTGGGCAGAATCAGA CC ACT (SEQ ID NO: 4024) (SEQ ID NO: 4022) (SEQ ID NO: 4023) hCV11225994 A/G TCCCAATCCCAGGACA CCCAATCCCAGGACG TGACATTGCACTCTCAA (SEQ ID NO: 4025) (SEQ ID NO: 4026) ATATTT (SEQ ID NO: 4027) hCV11231076 C/T AGTCATGGTGGACGGTG CAGTCATGGTGGACGGT CTTGGTGCTGTCCTCAC (SEQ ID NO: 4028) A TGTAGTA (SEQ ID NO: 4029) (SEQ ID NO: 4030) hCV11276368 C/T CGCGGAGTGTCAAGAGG CGCGGAGTGTCAAGAGA ACCTTGGGCAAAAAATA (SEQ ID NO: 4031) (SEQ ID NO: 4032) CAT (SEQ ID NO: 4033) hCV11315168 C/G GTTGTTTGCTTCATCTC GTTGTTTGCTTCATCTC AGTGCTGGGCTCAAGAA TGC TGG C (SEQ ID NO: 4034) (SEQ ID NO: 4035) (SEQ ID NO: 4036) hCV11315171 C/T ATTTCTGAATAACTGAA ATTTCTGAATAACTGAA CCCTACCTGGGTTATCA GTTGGTC GTTGGTT GTAAT (SEQ ID NO: 4037) (SEQ ID NO: 4038) (SEQ ID NO: 4039) hCV11398434 C/T AATGAAATCTAGGAATA CAATGAAATCTAGGAAT CTTCAGCCCAAGAGTTT GTGACCAC AGTGACCAT GAGACTA (SEQ ID NO: 4040) (SEQ ID NO: 4041) (SEQ ID NO: 4042) hCV11398437 C/T AGAGTATGTGTAATTAA AAGAGTATGTGTAATTA ACTGAGGATGAGTAATT GTCGCTAC AGTCGCTAT ATGTCTTATTAGGACCA (SEQ ID NO: 4043) (SEQ ID NO: 4044) TAG (SEQ ID NO: 4045) hCV11433557 G/C TGATGAGTGTCGAAATG TGATGAGTGTCGAAATG ACCGGTTCTGCTTTGAT GAG GAC AAC (SEQ ID NO: 4046) (SEQ ID NO: 4047) (SEQ ID NO: 4048) hCV11438723 C/T ACGCGTGTCTTTCTCAC ACGCGTGTCTTTCTCAT AAGTTACTTAAAATCTG (SEQ ID NO: 4049) (SEQ ID NO: 4050) CTTTTTCTTAG (SEQ ID NO: 4051) hCV11446935 G/T GGCTGAAATTATTCCAA GGCTGAAATTATTCCAA ACCAGGCTGTTGACCTT TAAAGGAC TAAAGGAA GCTATAA (SEQ ID NO: 4052) (SEQ ID NO: 4053) (SEQ ID NO: 4054) hCV11461296 C/G GACTGAGGCCCACGC GACTGAGGCCCACGG GGGTCTGCAGGTTAACA (SEQ ID NO: 4055) (SEQ ID NO: 4056) ACA (SEQ ID NO: 4057) hCV11466079 A/G CCCATACCCAAGGAACC CCCATACCCAAGGAACC GGATCAGCCAAGCCAGA TT TC CTT (SEQ ID NO: 4058) (SEQ ID NO: 4059) (SEQ ID NO: 4060) hCV11466848 A/G CTGGACTTCTGGGTCCT TGGACTTCTGGGTCCC CAAGAAGCTGAGCGAGT (SEQ ID NO: 4061) (SEQ ID NO: 4062) GTCT (SEQ ID NO: 4063) hCV11504800 A/T TAACAATTTGGTTTATA ACAATTTGGTTTATATC CAGCTCTACATAGTATC TCCTCCCT CTCCCA CTGGAGAGAC (SEQ ID NO: 4064) (SEQ ID NO: 4065) (SEQ ID NO: 4066) hCV11513719 C/T TCCTCCGGTGTCAGTTT TCCTCCGGTGTCAGTTT GCAGTGGCCAGGGTTCA AG AA T (SEQ ID NO: 4067) (SEQ ID NO: 4068) (SEQ ID NO: 4069) hCV11568668 A/G CTTTCACTCACTCAACA TTCACTCACTCAACACA GCTCAGTTGGGAGATGT CATACTTA TACTTG GTAGGTA (SEQ ID NO: 4070) (SEQ ID NO: 4071) (SEQ ID NO: 4072) hCV11592758 T/C CATCCAACAGCTCTTCT CATCCAACAGCTCTTCT CAAACATCCGAGGACAA ATCAT ATCAC G (SEQ ID NO: 4073) (SEQ ID NO: 4074) (SEQ ID NO: 4075) hCV11623551 C/T ACTCTTTGATGGCAACC TTAACTCTTTGATGGCA GGTTTTAAGCCAGCACT ATG ACCATA CTTAGACT (SEQ ID NO: 4076) (SEQ ID NO: 4077) (SEQ ID NO: 4078) hCV11628130 T/A CTGCCCTCTTTTTAGCA CTGCCCTCTTTTTAGCA CCCTTTCTCATTCATTC GA GT ATTTT (SEQ ID NO: 4079) (SEQ ID NO: 4080) (SEQ ID NO: 4081) hCV11642651 C/T AAGGATGGCCTCATCAG AAGGATGGCCTCATCAA CCAGGATGGAGATGAAG (SEQ ID NO: 4082) (SEQ ID NO: 4083) AGA (SEQ ID NO: 4084) hCV11678789 G/T CCACTGAAATGCTACTT CCACTGAAATGCTACTT AGACAATCTGAGACATG TGAGTAAC TGAGTAAA CGAAGACT (SEQ ID NO: 4085) (SEQ ID NO: 4086) (SEQ ID NO: 4087) hCV11688401 A/G CCCTTTCCCAGGCTTAT CCCTTTCCCAGGCTTAT CCTCAACCAGGAAGTCA T C GAG (SEQ ID NO: 4088) (SEQ ID NO: 4089) (SEQ ID NO: 4090) hCV11689916 A/T TGTGAGTGGGCCTTCAC GTGAGTGGGCCTTCACA GGAGCCCCGCTTCAT T (SEQ ID NO: 4092) (SEQ ID NO: 4093) (SEQ ID NO: 4091) hCV11697322 A/G CAGTTCGTGCTATTGAG CAGTTCGTGCTATTGAG CAAAGAAAAACAGATCA AAAAT AAAAC CACAGAT (SEQ ID NO: 4094) (SEQ ID NO: 4095) (SEQ ID NO: 4096) hCV11703905 C/T GCACAGAAAGCCGTGAG GCACAGAAAGCCGTGAA CTGTAAGCTCCTCTGGT (SEQ ID NO: 4097) (SEQ ID NO: 4098) TCAG (SEQ ID NO: 4099) hCV11761245 C/T ACACACTTCACAATGGA CACACACTTCACAATGG CAGTAAACCTGGCACTC CG ACA TTCAGTAGT (SEQ ID NO: 4100) (SEQ ID NO: 4101)  (SEQ ID NO: 4102) hCV11764545 G/T CGAAGCTTCCGAGGAAG CGAAGCTTCCGAGGAAT GACACCGGACGAGAGAG (SEQ ID NO: 4103) (SEQ ID NO: 4104) AC (SEQ ID NO: 4105) hCV11765753 A/G GAGAAAAAAGAACAGAT GAGAAAAAAGAACAGAT TGATGCCTCTCAGCATT GTCCTT GTCCTC TATAC (SEQ ID NO: 4106) (SEQ ID NO: 4107) (SEQ ID NO: 4108) hCV11846435 C/T GCTGGGAACCTCTATCC GCTGGGAACCTCTATCC GGGCTCATGAGGAAAGT C T TTATGTG (SEQ ID NO: 4109) (SEQ ID NO: 4110) (SEQ ID NO: 4111) hCV11854426 C/T CATAATGATGTTGGTAG CATAATGATGTTGGTAG CCAGATTGATTCATGCT GGTCG GGTCA CCTCTCAC (SEQ ID NO: 4112) (SEQ ID NO: 4113) (SEQ ID NO: 4114) hCV11856381 A/G CAATGGTGGGCATGTCT AATGGTGGGCATGTCTT GAGGGCTAAAGGAAAGA TAT AC GGTGTTCT (SEQ ID NO: 4115) (SEQ ID NO: 4116) (SEQ ID NO: 4117) hCV11864162 A/C CCCTTTGCCTTGTCGTT CCCTTTGCCTTGTCGTG CACTGCACCAGGCCTAG (SEQ ID NO: 4118) (SEQ ID NO: 4119) AAATAC (SEQ ID NO: 4120) hCV1188731 C/T GGCAGATAGTAGCTGTT GGCAGATAGTAGCTGTT TTTGGGTAGCAGATCAC CAATAAAC CAATAAAT TTCATTAATCTGA (SEQ ID NO: 4121) (SEQ ID NO: 4122) (SEQ ID NO: 4123) hCV1188735 C/T CTTGCTCTGATAAGAAC CCTTGCTCTGATAAGAA CTGCCGTGGCCTTTCAA TTTACAAC CTTTACAAT AG (SEQ ID NO: 4124) (SEQ ID NO: 4125) (SEQ ID NO: 4126) hCV1188747 C/G TGAAAATGTTCCTGAGC TGAAAATGTTCCTGAGC ACTATCACCCAGAAGGC TATGG TATGC GATCATAC (SEQ ID NO: 4127) (SEQ ID NO: 4128) (SEQ ID NO: 4129) hCV11955747 A/C AAAGGGAAGGAGGTTAC AGGGAAGGAGGTTACTT TCCTCTGTGGAGAGGGA TTACT ACG TAC (SEQ ID NO: 4130) (SEQ ID NO: 4131) (SEQ ID NO: 4132) hCV11960994 A/G TTTGTAAACACACAGAG TTTGTAAACACACAGAG TTTCCGCTCGACATGTA ATGATAAT ATGATAAC A (SEQ ID NO: 4133) (SEQ ID NO: 4134) (SEQ ID NO: 4135) hCV11972326 C/G TTCTTTTAAAGGATTGG TTCTTTTAAAGGATTGG AGAGCAGAACGAGGTTT TAAACTC TAAACTG TATTT (SEQ ID NO: 4136) (SEQ ID NO: 4137) (SEQ ID NO: 4138) hCV12020339 G/T GGACCCCCGAAGGC TGGACCCCCGAAGGA GGCCCCAACAGTTGACT (SEQ ID NO: 4139) (SEQ ID NO: 4140) G (SEQ ID NO: 4141) hCV12022345 A/T AGTGGCCTCATCCTCCT GTGGCCTCATCCTCCA GAACGCTTACGAGCCTT (SEQ ID NO: 4142) (SEQ ID NO: 4143) ATC (SEQ ID NO: 4144) hCV12034662 A/G GGGGCTATGTAGACTAC GGGCTATGTAGACTACA TTCAACAATGCGTTGGC ATCTTTA TCTTTG AAGAGAT (SEQ ID NO: 4145) (SEQ ID NO: 4146) (SEQ ID NO: 4147) hCV12107274 C/T TGATGCTAATCTGTTCT TCTGATGCTAATCTGTT ATAACAAGAGGAAGGAG CTGTG CTCTGTA ATCAGA (SEQ ID NO: 4148) (SEQ ID NO: 4149) (SEQ ID NO: 4150) hCV12108469 A/G TCGTGTCTACCTTAGGG CGTGTCTACCTTAGGGT CGTATGGCTTCAGGATG TACA ACG TC (SEQ ID NO: 4151) (SEQ ID NO: 4152) (SEQ ID NO: 4153) hCV1239369 A/C GAAGATGTTACTCCTAA AAGATGTTACTCCTAAT GTTGTACCCTCATTGTG TATCATACAGT ATCATACAGG ACATTAGGT (SEQ ID NO: 4154) (SEQ ID NO: 4155) (SEQ ID NO: 4156) hCV1243283 A/G TTATTCCTAGTTCCAAT TTATTCCTAGTTCCAAT GCCTCTTGGGAGTACTC GAAAGAT GAAAGAC ACTT (SEQ ID NO: 4157) (SEQ ID NO: 4158) (SEQ ID NO: 4159) hCV1253630 A/G TCGCAGGTGTCCCTA CGCAGGTGTCCCTG CCCCATCCCTTCTCA (SEQ ID NO: 4160) (SEQ ID NO: 4161) (SEQ ID NO: 4162) hCV1323634 C/T GAAGTGAAATAATGGTT GAAGTGAAATAATGGTT CTGCATCTGTTGAGATT CAGCATAC CAGCATAT ATTGTATGACGTT (SEQ ID NO: 4163) (SEQ ID NO: 4164) (SEQ ID NO: 4165) hCV1323669 A/G GTGTTATACTGTATCAC TGTTATACTGTATCACT GGGGGCGGAACTTAGAC TCTTCTTTTCTAA CTTCTTTTCTAG A (SEQ ID NO: 4166) (SEQ ID NO: 4167) (SEQ ID NO: 4168) hCV1345898 C/T CAGTTTTCCATGGGTTC CAGTTTTCCATGGGTTC TTATGAAATGGTACAGA TACTAC TACTAT CAAGTGAT (SEQ ID NO: 4169) (SEQ ID NO: 4170) (SEQ ID NO: 4171) hCV1361979 A/G CCAGTTTTGGTGTCAAC CCAGTTTTGGTGTCAAC TTGCAACCTGAAAAACA TAGAAA TAGAAG TAACTA (SEQ ID NO: 4172) (SEQ ID NO: 4173) (SEQ ID NO: 4174) hCV1366867 A/G GGAGCCAGGCCTACAT GGAGCCAGGCCTACAC CGCCTCGACGAGATTCT (SEQ ID NO: 4175) (SEQ ID NO: 4176) (SEQ ID NO: 4177) hCV1375141 C/T CCTTCGGAGTTGCACAG CCTTCGGAGTTGCACAA TTTTTGGTGGGTTTCTC (SEQ ID NO: 4178) (SEQ ID NO: 4179) TGTA (SEQ ID NO: 4180) hCV1415464 C/G CCCTGGGGGTCTTTC CCCTGGGGGTCTTTG CCGTGGCCTCTGTGATT (SEQ ID NO: 4181) (SEQ ID NO: 4182) (SEQ ID NO: 4183) hCV1449414 T/C ACACACATATGGTGGTT CACACATATGGTGGTTC CATGTCCCAGCTCTTCT CATAAT ATAAC TG (SEQ ID NO: 4184) (SEQ ID NO: 4185) (SEQ ID NO: 4186) hCV1449416 T/A TATGCAAGGTGTTGTTA GTATGCAAGGTGTTGTT GCGTTGTAACTGAGTTC TAGATTT ATAGATTA ATTATTC (SEQ ID NO: 4187) (SEQ ID NO: 4188) (SEQ ID NO: 4189) hCV1463112 C/T TTCAAGCTATTTGTAGT CTTCAAGCTATTTGTAG GGTGTGGCCTTCTTTGG TCCTAGAG TTCCTAGAA AAGATC (SEQ ID NO: 4190) (SEQ ID NO: 4191) (SEQ ID NO: 4192) hCV1463184 C/T GGTTAAATGACACTCTT GGTTAAATGACACTCTT GTTTCAGAAAGATTTGT TGGGG TGGGA CAGGACCACT (SEQ ID NO: 4193) (SEQ ID NO: 4194) (SEQ ID NO: 4195) hCV1463222 C/T TGTTTCTCCCACATATT CTGTTTCTCCCACATAT CGCTACATCACTCAGCT CACATAC TCACATAT CATGAAA (SEQ ID NO: 4196) (SEQ ID NO: 4197) (SEQ ID NO: 4198) hCV1463224 C/T CAACTCACACGGGAAGA CAACTCACACGGGAAGA GTGAATATGTGGGAGAA C T ACAGCACTAG (SEQ ID NO: 4199) (SEQ ID NO: 4200) (SEQ ID NO: 4201) hCV1463226 C/T ATTTCCTCCCTCACATG ATTTCCTCCCTCACATG TCAAAGAATGAAGAGTG ATAC ATAT AAGACA (SEQ ID NO: 4202) (SEQ ID NO: 4203) (SEQ ID NO: 4204) hCV1488444 G/T TCAACAGAATGCCATGA GTCAACAGAATGCCATG CAAGGCAGAAGTAGTTG GC AGA TCCAACAG (SEQ ID NO: 4205) (SEQ ID NO: 4206) (SEQ ID NO: 4207) hCV1489995 C/G GAGGCGAAAGGAACAGA GAGGCGAAAGGAACAGA GCGTGCTGAGGAGTAAT G C GTAC (SEQ ID NO: 4208) (SEQ ID NO: 4209) (SEQ ID NO: 4210) hCV1550877 C/T GGTCCAAATAGACTAAC GGTCCAAATAGACTAAC CCCACACAACATACAAT TTTAAGTGAC TTTAAGTGAT TTACAAATGC (SEQ ID NO: 4211) (SEQ ID NO: 4212) (SEQ ID NO: 4213) hCV1552894 A/G CAGATTCAGCCTCCCAA CAGATTCAGCCTCCCAG GCAGTTGGAAATCTGAA (SEQ ID NO: 4214) (SEQ ID NO: 4215) TTTC (SEQ ID NO: 4216) hCV1552900 A/G GGGATGGAAGAGCTTCA GGGATGGAAGAGCTTCG CTGCAGCCTTCCTCTGA (SEQ ID NO: 4217) (SEQ ID NO: 4218) C (SEQ ID NO: 4219) hCV15746640 A/G GAAACGGCTGGTTTGTG AACGGCTGGTTTGTGC TCCAATCTACCTTTTCC T (SEQ ID NO: 4221) TTGTATT (SEQ ID NO: 4220) (SEQ ID NO: 4222) hCV15752705 C/G GCCTCCCCTGCTGC GGCCTCCCCTGCTGG AGGTCCCTTCTGCTGTA (SEQ ID NO: 4223) (SEQ ID NO: 4224) ATG (SEQ ID NO: 4225) hCV15752716 C/T ACGCTGCTGTTCCG CACGCTGCTGTTCCA CAGACAGACAACAATTC (SEQ ID NO: 4226) (SEQ ID NO: 4227) AGAAGAA (SEQ ID NO: 4228) hCV15758290 G/A GTCACACACCCAGGAGC GGTCACACACCCAGGAG GGATGATTGCCATAATG (SEQ ID NO: 4229) T AGTC (SEQ ID NO: 4230) (SEQ ID NO: 4231) hCV15760070 A/T TGTCCAGATCCACATAG TTGTCCAGATCCACATA CTTTATGCAGCGGACCA AACA GAACT T (SEQ ID NO: 4232) (SEQ ID NO: 4233) (SEQ ID NO: 4234) hCV15770510 C/T ACGGCATCTTCTATCCG CACGGCATCTTCTATCC CCAGCTGGTGGTGAGTG (SEQ ID NO: 4235) A (SEQ ID NO: 4237) (SEQ ID NO: 4236) hCV15851335 C/T GATGGCATGGATGGC GGATGGCATGGATGGT GCAGGATGTGCTGTGAT (SEQ ID NO: 4238) (SEQ ID NO: 4239) TAT (SEQ ID NO: 4240) hCV15851779 A/G CAACCTGACATGGAAGA CAACCTGACATGGAAGA GATGTGGTGGGATTTGA AAT AAC CAT (SEQ ID NO: 4241) (SEQ ID NO: 4242) (SEQ ID NO: 4243) hCV15870728 C/T GAGAGAGAACAGCCAGA GAGAGAGAACAGCCAGA GCATCCCAGGTCAAGGT C T A (SEQ ID NO: 4244) (SEQ ID NO: 4245) (SEQ ID NO: 4246) hCV15871150 A/G CCCAAATTCTGCATAGC CCCAAATTCTGCATAGC GTGGGCTCGGGTCTCTA ATAA ATAG (SEQ ID NO: 4249) (SEQ ID NO: 4247) (SEQ ID NO: 4248) hCV15874689 A/G TGGAAAGCCTCAAGTCT GGAAAGCCTCAAGTCC TTCTAGAGGTGGTCAGC (SEQ ID NO: 4250) (SEQ ID NO: 4251) TAATACTT (SEQ ID NO: 4252) hCV15876011 T/G ACCATCAGTTACCTTCA CATCAGTTACCTTCATG GCGGACCACCTGTTAAT TGACT ACG C (SEQ ID NO: 4253) (SEQ ID NO: 4254) (SEQ ID NO: 4255) hCV15882274 G/A CATGGAGATCCAAGTCG ACATGGAGATCCAAGTC GACTCAGGCAGGACAAC (SEQ ID NO: 4256) A C (SEQ ID NO: 4257) (SEQ ID NO: 4258) hCV15885004 A/G CTCCCCTACTCTGCTCA CTCCCCTACTCTGCTCA CATTCTCCCCACCAGGC TATAT TATAC ATTTAT (SEQ ID NO: 4259) (SEQ ID NO: 4260) (SEQ ID NO: 4261) hCV15892430 C/T ACTGAGAGCTTGTCCTC ACTGAGAGCTTGTCCTC CACACCCAGAGACCACA AG AA GG (SEQ ID NO: 4262) (SEQ ID NO: 4263) (SEQ ID NO: 4264) hCV15954277 A/G TGTCGGTAAACATGGCA GTCGGTAAACATGGCG GGTGGGTGGTCTGACTC (SEQ ID NO: 4265) (SEQ ID NO: 4266) TC (SEQ ID NO: 4267) hCV15954645 A/T CTGATGGTATTTTACAG CTGATGGTATTTTACAG AAGACGCAACGAGCTTT TGGATCA TGGATCT GTGT (SEQ ID NO: 4268) (SEQ ID NO: 4269) (SEQ ID NO: 4270) hCV15955388 C/T TGCATTACTCGGACCC CTGCATTACTCGGACCT TGCCCGCACCTTGTC (SEQ ID NO: 4271) (SEQ ID NO: 4272) (SEQ ID NO: 4273) hCV15963535 C/G GTTGCTCATAGTTGCTG GTTGCTCATAGTTGCTG CAGCATCTTCGACAGAG GC GG ACA (SEQ ID NO: 4274) (SEQ ID NO: 4275) (SEQ ID NO: 4276) hCV15963962 A/G TACTGTCCCGTGTTCCA CTGTCCCGTGTTCCG CTCTCCCAGAGCCCTCT (SEQ ID NO: 4277) (SEQ ID NO: 4278) AG (SEQ ID NO: 4279) hCV15963994 G/T GCTGCGTTTCTACTCTG TGCTGCGTTTCTACTCT ACTCATGCGCATGCACA C GA TAAACA (SEQ ID NO: 4280) (SEQ ID NO: 4281) (SEQ ID NO: 4282) hCV15965796 C/G CGCCCTGCACTTTCAC CGCCCTGCACTTTCAG CCGTGCTCTACTGCTTC (SEQ ID NO: 4283) (SEQ ID NO: 4284) TCTA (SEQ ID NO: 4285) hCV15967490 C/T TGGAGGGTCCAACTCAT TGGAGGGTCCAACTCAT GGGATTGCTCAGCATCT AAC AAT CCTTAAAT (SEQ ID NO: 4286) (SEQ ID NO: 4287) (SEQ ID NO: 4288) hCV15973230 A/G TCACTGATGTCAATGAA ACTGATGTCAATGAACA CCCATCCCAGAGTTCTT CACT CC GTC (SEQ ID NO: 4289) (SEQ ID NO: 4290) (SEQ ID NO: 4291) hCV1600754 C/T ATTTCCCTGGGAAGACT ATTTCCCTGGGAAGACT CTAGTGGTGGAAGGAAA TC TT TGTTA (SEQ ID NO: 4292) (SEQ ID NO: 4293) (SEQ ID NO: 4294) hCV1603697 C/T CGGCCTGCGTGGAC CGGCCTGCGTGGAT GCCCAGGGCGTGTTCT (SEQ ID NO: 4295) (SEQ ID NO: 4296) (SEQ ID NO: 4297) hCV16044337 A/G TCCGGGTGCACGTATA CGGGTGCACGTATG TGGAGAGTGTTTGCTCA (SEQ ID NO: 4298) (SEQ ID NO: 4299) TCTAC (SEQ ID NO: 4300) hCV16047108 A/G TGTTTTCATCCACTTGA TTTTCATCCACTTGAAC CAATTTTGGCTCCCTTA ACTGT TGC AAAG (SEQ ID NO: 4301) (SEQ ID NO: 4302) (SEQ ID NO: 4303) hCV16065831 C/T CTCCTGACTGTGAACAA CTCCTGACTGTGAACAA CCCCCAGTTGTGCATAC CTTATC CTTATT AC (SEQ ID NO: 4304) (SEQ ID NO: 4305) (SEQ ID NO: 4306) hCV16140621 A/T AGCTGAAAGGAGAAGTC AGCTGAAAGGAGAAGTC CCCTGCTACGAAGGTGG AGT AGA AATATCT (SEQ ID NO: 4307) (SEQ ID NO: 4308) (SEQ ID NO: 4309) hCV16172339 A/T CTGCGGCTCCACCT TGCGGCTCCACCA TGGCATCTGCCATACTC (SEQ ID NO: 4310) (SEQ ID NO: 4311) A (SEQ ID NO: 4312) hCV16173091 T/C CACAGACTTGATGTTTT CAGACTTGATGTTTTTG TGCAAAGGAAGCAACTT TGAAAGT AAAGC CA (SEQ ID NO: 4313) (SEQ ID NO: 4314) (SEQ ID NO: 4315) hCV16179493 C/T GGGTCCGGCCACAC GGGTCCGGCCACAT GGGCCCCTCAGTGAAG (SEQ ID NO: 4316) (SEQ ID NO: 4317) (SEQ ID NO: 4318) hCV16179599 C/T CTGCTCTCAGAACCTCA CTGCTCTCAGAACCTCA CACTGCAGGGAAATAGA GTC GTT GAAA (SEQ ID NO: 4319) (SEQ ID NO: 4320) (SEQ ID NO: 4321) hCV16179628 A/G CAGGTTCACTGTTTCTC CAGGTTCACTGTTTCTC GAGCACATCCTTCCATT CAAT CAAC GTAA (SEQ ID NO: 4322) (SEQ ID NO: 4323) (SEQ ID NO: 4324) hCV16182835 A/G TGTTCTTCCTTATGATG GTTCTTCCTTATGATGA GGCGTTCCTCTCACCTT ATGT TGC AATA (SEQ ID NO: 4325) (SEQ ID NO: 4326) (SEQ ID NO: 4327) hCV16186452 C/T GGCACCCCCGACAG GGCACCCCCGACAA TCCTTATGCTCTCAGTG (SEQ ID NO: 4328) (SEQ ID NO: 4329) AAGTTC (SEQ ID NO: 4330) hCV16189421 C/T GCCATCATTTGCTTCTA GCCATCATTTGCTTCTA GCTTATTTGCCAGAAAA ACAC ACAT CATTT (SEQ ID NO: 4331) (SEQ ID NO: 4332) (SEQ ID NO: 4333) hCV16192174 G/A GAGCACCTTAACTATAG TGAGCACCTTAACTATA CTTGTCAAGGCACAGAA ATGGTG GATGGTA TAATT (SEQ ID NO: 4334) (SEQ ID NO: 4335) (SEQ ID NO: 4336) hCV16196618 C/G ATTAGCCCCAAAGCGTA ATTAGCCCCAAAGCGTA GCTTTAGAAGGCTGGAT C G ATTTATG (SEQ ID NO: 4337) (SEQ ID NO: 4338) (SEQ ID NO: 4339) hCV1639938 A/C AGTGGAGCTTCAGGGCT TGGAGCTTCAGGGCG CAGTGGAGACAGAGGAT (SEQ ID NO: 4340) (SEQ ID NO: 4341) GTTTAC (SEQ ID NO: 4342) hCV1643239 C/T CCAGAGTCCACAGAAAG CCAGAGTCCACAGAAAG GAAAATAACGCAAGCAG TTTC TTTT TTTC (SEQ ID NO: 4343) (SEQ ID NO: 4344) (SEQ ID NO: 4345) hCV1647371 C/T CTGGCTGGGTCACTAAC GCTGGCTGGGTCACTAA CCTCACCTGCATTCACA C CT TTT (SEQ ID NO: 4346) (SEQ ID NO: 4347) (SEQ ID NO: 4348) hCV1682755 C/T TGTTCTCAATGAATCAA CATGTTCTCAATGAATC GTCTTCCCCATGTTCAT AGCTATTAC AAAGCTATTAT ACTCTTGT (SEQ ID NO: 4349) (SEQ ID NO: 4350) (SEQ ID NO: 4351) hCV1690777 A/G GGCTTTACAGAAGGAAA GCTTTACAGAAGGAAAT GCATGCGCTGAATTTTA TGCT GCC TATAG (SEQ ID NO: 4352) (SEQ ID NO: 4353) (SEQ ID NO: 4354) hCV1729928 A/G GGAAATTGTTGAGTGTT GGAAATTGTTGAGTGTT CAATGCCCAAAGTTGGC TGTAAAGT TGTAAAGC TATGATT (SEQ ID NO: 4355) (SEQ ID NO: 4356) (SEQ ID NO: 4357) hCV1741111 C/T CCTCAGAATGGCCAAAA CCTCAGAATGGCCAAAA CCAGGCAGCCAGACTTC AC AT T (SEQ ID NO: 4358) (SEQ ID NO: 4359) (SEQ ID NO: 4360) hCV1770462 A/G GCACCTCTGGGTGAAGA CACCTCTGGGTGAAGAA GGCACAGGCAAGTCTGA ATA TG TT (SEQ ID NO: 4361) (SEQ ID NO: 4362) (SEQ ID NO: 4363) hCV1782711 C/T CCACTGCTGCAAGGAGT CCACTGCTGCAAGGAGT GCAGTCATCATATGGAC C T AACTTAC (SEQ ID NO: 4364) (SEQ ID NO: 4365) (SEQ ID NO: 4366) hCV1801149 A/G GAGAGTCGCAGGGTATT GAGAGTCGCAGGGTATT AAAGGCCCAGGCTCTAG TTAA TTAG A (SEQ ID NO: 4367) (SEQ ID NO: 4368) (SEQ ID NO: 4369) hCV1802755 C/T CTCCTTAAGAAGAATGC TCTCCTTAAGAAGAATG AGCCAGTTTAGCATTTA CACC CCACT CTCTTTACAAG (SEQ ID NO: 4370) (SEQ ID NO: 4371) (SEQ ID NO: 4372) hCV1843175 A/C CCCCGAAGCCTATGGCT CCCGAAGCCTATGGCG CGTCAGCACCCAACTCT (SEQ ID NO: 4373) (SEQ ID NO: 4374) G (SEQ ID NO: 4375) hCV1844077 A/G CCCTAAATGCAGAAATT CCCTAAATGCAGAAATT CCCTCTGAAATGCTGCT GAATCTT GAATCTC GTAACT (SEQ ID NO: 4376) (SEQ ID NO: 4377) (SEQ ID NO: 4378) hCV1948599 A/C GCAGTTTGAGTATAAAT GCAGTTTGAGTATAAAT CAGTGACAGATGAGTGC TGTTTGACTA TGTTTGACTC AGAGAAT (SEQ ID NO: 4379) (SEQ ID NO: 4380) (SEQ ID NO: 4381) hCV2002654 C/G GGAGCCCCAGGAAAG GGAGCCCCAGGAAAC AGAGCCCTCGGTTCTTG (SEQ ID NO: 4382) (SEQ ID NO: 4383) (SEQ ID NO: 4384) hCV2038 G/A CACGGCGGTCATGTG CCACGGCGGTCATGTA GGTGGAGCTTGGTTTCT (SEQ ID NO: 4385) (SEQ ID NO: 4386) CA (SEQ ID NO: 4387) hCV207123 C/G TGTAGATCATGTGGATG AATGTAGATCATGTGGA CTGTCAGGCTGTCTGTA GATTG TGGATTC AGTCTCTAT (SEQ ID NO: 4388) (SEQ ID NO: 4389) (SEQ ID NO: 4390) hCV2091644 C/T TTCTGGGGCATACAACG CTTCTGGGGCATACAAC AGGGACAACCCTCCATA (SEQ ID NO: 4391) A AA (SEQ ID NO: 4392) (SEQ ID NO: 4393) hCV2091649 A/G CCTCAGAGTATGTGCCC CCTCAGAGTATGTGCCC GCCCGGCTGCATCTAGT A G T (SEQ ID NO: 4394) (SEQ ID NO: 4395) (SEQ ID NO: 4396) hCV2091650 C/T TCTCTGAGCTGAGTGCC GTCTCTGAGCTGAGTGC TCCCTATCCTAACTCTC (SEQ ID NO: 4397) T CTTGTCT (SEQ ID NO: 4398) (SEQ ID NO: 4399) hCV2091669 A/T GTCAGTAGCGCTCACTT GTCAGTAGCGCTCACTT GGCTACTTAGCTGCAGT TT TA TCAAACTC (SEQ ID NO: 4400) (SEQ ID NO: 4401) (SEQ ID NO: 4402) hCV2091674 G/T CCACTTAATAACAACAC GCCACTTAATAACAACA GACTGAGCCTGTTTCCT TACTTGC CTACTTGA CACCTATAA (SEQ ID NO: 4403) (SEQ ID NO: 4404) (SEQ ID NO: 4405) hCV2143205 A/G TGTCGAATGGGAGTCTT TGTCGAATGGGAGTCTT CCTAGTAGTACAACGGA CTT CTC AGAAACAG (SEQ ID NO: 4406) (SEQ ID NO: 4407) (SEQ ID NO: 4408) hCV2146578 C/T CCTCCTAGAGAAGATCT CCTCCTAGAGAAGATCT AAGGCCCCTCTTCTGTC GCAC GCAT T (SEQ ID NO: 4409) (SEQ ID NO: 4410) (SEQ ID NO: 4411) hCV2146579 A/C TTCCTAACAGAGGCTTG TCCTAACAGAGGCTTGG TGCAGTGTCCCCTAGAA GA C TG (SEQ ID NO: 4412) (SEQ ID NO: 4413) (SEQ ID NO: 4414) hCV2192261 C/T CCTACCTTGAATTCACC CCTACCTTGAATTCACC CATTTCCAAATCAGAAA TATCTG TATCTA CATGA (SEQ ID NO: 4415) (SEQ ID NO: 4416) (SEQ ID NO: 4417) hCV2195496 C/T GCACCTCACAAACACCG TGCACCTCACAAACACC GCCTCTTCTGCAAATGG (SEQ ID NO: 4418) A ATGATATACAC (SEQ ID NO: 4419) (SEQ ID NO: 4420) hCV2221541 C/T CCTGGAGTGGATGCCTT CCTGGAGTGGATGCCTT GGACAGCAGACACCTGA C T GC (SEQ ID NO: 4421) (SEQ ID NO: 4422) (SEQ ID NO: 4423) hCV22271999 C/T GAGCACCTTAACTATAG TGAGCACCTTAACTATA CTTGTCAAGGCACAGAA ATGGTG GATGGTA TAATT (SEQ ID NO: 4424) (SEQ ID NO: 4425) (SEQ ID NO: 4426) hCV22273354 A/G CAGGTCAGGCACAAACA CAGGTCAGGCACAAACA GAAGATGACCTGTTGAG T C TCAGTA (SEQ ID NO: 4427) (SEQ ID NO: 4428) (SEQ ID NO: 4429) hCV22274594 G/A ACAACAGGAGCACACCG GACAACAGGAGCACACC GATGCAGTCCCTTTTTC (SEQ ID NO: 4430) A TAAA (SEQ ID NO: 4431) (SEQ ID NO: 4432) hCV22274679 C/T TATCGCTGGGTAAACCG GTATCGCTGGGTAAACC CGACTCTGAGGAGATGG (SEQ ID NO: 4433) A AGTAT (SEQ ID NO: 4434) (SEQ ID NO: 4435) hCV22274761 A/G ACTCCCCCAAGATCTTC CCCCCAAGATCTTCC GCTCCCCCGACAAACT T (SEQ ID NO: 4437) (SEQ ID NO: 4438) (SEQ ID NO: 4436) hCV22275550 C/T CCATCTGTTCCGCCG TCCATCTGTTCCGCCA TTACCCAGCAGCGAAGA (SEQ ID NO: 4439) (SEQ ID NO: 4440) C (SEQ ID NO: 4441) hCV22303 A/G AGCTTGGTTGTAGCCCA GCTTGGTTGTAGCCCG AGGCCAGCCTCCAAATC (SEQ ID NO: 4442) (SEQ ID NO: 4443) TTTC (SEQ ID NO: 4444) hCV2230606 A/G AAATGTTGTCAACGTCC AATGTTGTCAACGTCCG AGTCACTGGCAGCAATG A (SEQ ID NO: 4446) AT (SEQ ID NO: 4445) (SEQ ID NO: 4447) hCV2275263 A/T GTCCATCAGCAAATTGT GTCCATCAGCAAATTGT CCGATGACCTGGGGACA CTCT CTCA TATTAG (SEQ ID NO: 4448) (SEQ ID NO: 4449) (SEQ ID NO: 4450) hCV2275272 C/T CCTTTCCTTGTCTGTCT CCTTTCCTTGTCTGTCT GAAGGAGGGGGAGGAAT GC GT GACT (SEQ ID NO: 4451) (SEQ ID NO: 4452) (SEQ ID NO: 4453) hCV2275273 A/G AGAGGTCAGCACTTACA AGAGGTCAGCACTTACA CAAGCAAGCATAGACCA GTT GTC GATAT (SEQ ID NO: 4454) (SEQ ID NO: 4455) (SEQ ID NO: 4456) hCV2275276 A/G CCATTCACATACAAATC CCATTCACATACAAATC CCAGATGAAACTTCTTC TTTCTTACT TTTCTTACC CTGGTCATT (SEQ ID NO: 4457) (SEQ ID NO: 4458) (SEQ ID NO: 4459) hCV2276802 A/C TGGCTCAAGACCAAT TGGCTCAAGACCAAG CCCACATCCTTGCTGAT (SEQ ID NO: 4460) (SEQ ID NO: 4461) C (SEQ ID NO: 4462) hCV2310409 A/T CTCAGGGAGGGAGAGAG CTCAGGGAGGGAGAGAG ACAGCTCAGGCAGAAAC A T TG (SEQ ID NO: 4463) (SEQ ID NO: 4464) (SEQ ID NO: 4465) hCV2335281 G/T CAGCCTAGGCAGCATTG CAGCCTAGGCAGCATTT CCTGGGTTCAACCTTCT (SEQ ID NO: 4466) (SEQ ID NO: 4467) GAGTAGAT (SEQ ID NO: 4468) hCV2485037 A/G TGCAAGAGGACTAAGCA GCAAGAGGACTAAGCAT GCGGCCTTGCACTCA TGA GG (SEQ ID NO: 4471) (SEQ ID NO: 4469) (SEQ ID NO: 4470) hCV2503034 A/C ACGACAGGATCCTGAAT CGACAGGATCCTGAATG CCTAGCTCGTACCCACC GA C TCT (SEQ ID NO: 4472) (SEQ ID NO: 4473) (SEQ ID NO: 4474) hCV2531086 A/G GCCCCCCTCTCTGAAGA CCCCCCTCTCTGAAGG CCAGTTCGTGGTATGTT (SEQ ID NO: 4475) (SEQ ID NO: 4476) CATCT (SEQ ID NO: 4477) hCV2531730 T/A CATTTGGCTATTTTTAG ACATTTGGCTATTTTTA GCGGCTGGGTTTCTGT CTCTAAA GCTCTAAT (SEQ ID NO: 4480) (SEQ ID NO: 4478) (SEQ ID NO: 4479) hCV2536595 A/G CATCCCGCGCCAT CATCCCGCGCCAC CCTCCAGAGAAGAAGAA (SEQ ID NO: 4481) (SEQ ID NO: 4482) GACAC (SEQ ID NO: 4483) hCV25472345 C/T GGTCACAGCCAGGC AGGTCACAGCCAGGT CCCCAGGAATATGTAAG (SEQ ID NO: 4484) (SEQ ID NO: 4485) TTGA (SEQ ID NO: 4486) hCV25472673 C/T TGGGCTCCATCCCAC TGGGCTCCATCCCAT CCAATTCTTTTTCTTCT (SEQ ID NO: 4487) (SEQ ID NO: 4488) TTCAGTT (SEQ ID NO: 4489) hCV25473098 A/G CACAGACTTGATGTTTT CAGACTTGATGTTTTTG TGCAAAGGAAGCAACTT TGAAAGT AAAGC CA (SEQ ID NO: 4490) (SEQ ID NO: 4491) (SEQ ID NO: 4492) hCV25474101 C/T GCTGCTATTTTTGTTAT GCTGCTATTTTTGTTAT GGCCTTACCATCTCCAG TATTATTTTCTAC TATTATTTTCTAT AAA (SEQ ID NO: 4493) (SEQ ID NO: 4494) (SEQ ID NO: 4495) hCV2553030 C/T CCGGCTTGCACTTCAC CCGGCTTGCACTTCAT CTTTGTGGCCGCAGTAG (SEQ ID NO: 4496) (SEQ ID NO: 4497) T (SEQ ID NO: 4498) hCV2554615 C/G GCTCAGTCATTACCTTT GCTCAGTCATTACCTTT ACTGCTCCCTCCCATTC GCC GCG ATACAG (SEQ ID NO: 4499) (SEQ ID NO: 4500) (SEQ ID NO: 4501) hCV2554721 A/G TTAATTCTTTTGGCACA ATTCTTTTGGCACAGGT TGACTGGGGAGAAGTGA GGTAGA AGG GAACTAGA (SEQ ID NO: 4502) (SEQ ID NO: 4503) (SEQ ID NO: 4504) hCV2557331 C/T GGGGCCATTTATTCTTC GGGGCCATTTATTCTTC GGAGTGGAAGGAATGGG TTCAC TTCAT GATTAAAG (SEQ ID NO: 4505) (SEQ ID NO: 4506) (SEQ ID NO: 4507) hCV2557469 A/C TGCTGGTGGCTTTAAAG TGCTGGTGGCTTTAAAG GGCAAAACCCCTTTTAT AA AC TG (SEQ ID NO: 4508) (SEQ ID NO: 4509) (SEQ ID NO: 4510) hCV25591528 A/G TCCAAAAGGACCTGACA TCCAAAAGGACCTGACA GGCTGCAGAATGGAATT T C T (SEQ ID NO: 4511) (SEQ ID NO: 4512) (SEQ ID NO: 4513) hCV25596880 C/G CCTAGACAATAAAGATG CCTAGACAATAAAGATG CCAACTCTCTTCCTCTT GTCCTC GTCCTG GTCAT (SEQ ID NO: 4514) (SEQ ID NO: 4515) (SEQ ID NO: 4516) hCV25598594 A/G ATATATTGACCGTTCTC ATATATTGACCGTTCTC GCCACCTCCAACCATAT CCAT CCAC C (SEQ ID NO: 4517) (SEQ ID NO: 4518) (SEQ ID NO: 4519) hCV25603879 C/T GAAGTCATTCTGCTCTG ATGAAGTCATTCTGCTC TTTCCATCTCCTAACTC C TGT TTTTCTAG (SEQ ID NO: 4520) (SEQ ID NO: 4521) (SEQ ID NO: 4522) hCV25605897 G/T AAGGCAGGATGGGAGTG AAAGGCAGGATGGGAGT CGTCAAAGCACTAATGT (SEQ ID NO: 4523) T CATGT (SEQ ID NO: 4524) (SEQ ID NO: 4525) hCV25607193 C/T GCGCAAAAGGCAAGAC GCGCAAAAGGCAAGAT CCTTGGGACACACATTT (SEQ ID NO: 4526) (SEQ ID NO: 4527) ACAG (SEQ ID NO: 4528) hCV25608818 A/G CTCAATGTCGTATTCAC CAATGTCGTATTCACCT ACTCCAGGATTTTTCAA CTTCT TCC AGATTAT (SEQ ID NO: 4529) (SEQ ID NO: 4530) (SEQ ID NO: 4531) hCV25609975 A/C CTTTGAACCTTTTCACC TTTGAACCTTTTCACCA GAGTGAGGAGGGAGAAA ACA CC GTAAG (SEQ ID NO: 4532) (SEQ ID NO: 4533) (SEQ ID NO: 4534) hCV25610470 A/G CACAATCACCACGGTCT ACAATCACCACGGTCC CCTTCTGCATCAGCATC (SEQ ID NO: 4535) (SEQ ID NO: 4536) TTC (SEQ ID NO: 4537) hCV25610774 C/T GGGTCGGTGCAAGAGG  GGGTCGGTGCAAGAGA  GCACCTTGGTGGGTTTG  (SEQ ID NO: 4538) (SEQ ID NO: 4539) T (SEQ ID NO: 4540) hCV25610819 A/T GGACGTGGACATGGAGT  GGACGTGGACATGGAGA  CGGCGCTCGTAGGTG (SEQ ID NO: 4541) (SEQ ID NO: 4542) (SEQ ID NO: 4543) hCV25614016 A/G AGTGGCCAAGAACACCA  TGGCCAAGAACACCG  GGTATGAGGCAAAGTTC (SEQ ID NO: 4544) (SEQ ID NO: 4545) CTG (SEQ ID NO: 4546) hCV25617571 C/T CCAGCAGTATGGACG  TGCCAGCAGTATGGACA CCATCCAGCCTCAGGAA (SEQ ID NO: 4547) (SEQ ID NO: 4548) C (SEQ ID NO: 4549) hCV25618493 G/A GAGGCTGCGTATCC  GGAGGCTGCGTATCT  GTAGCTGTGCAGTGACA (SEQ ID NO: 4550) (SEQ ID NO: 4551) GTGT (SEQ ID NO: 4552) hCV25623265 A/G TGGAGGCTGATGGGTA  GGAGGCTGATGGGTG  CGCTTTGCAGCCATAAC (SEQ ID NO: 4553) (SEQ ID NO: 4554) T (SEQ ID NO: 4555) hCV25629396 C/G AGAACGCCTATGAGGAG AAGAACGCCTATGAGGA TTGGGTGGCACCATATG TG  GTC  (SEQ ID NO: 4558) (SEQ ID NO: 4556) (SEQ ID NO: 4557) hCV25629476 A/G ATCTCCTCGGCTGTCTT  ATCTCCTCGGCTGTCTC  AACCTCACCTGGCATGA (SEQ ID NO: 4559) (SEQ ID NO: 4560) G (SEQ ID NO: 4561) hCV25629492 A/G CCCACAGCCTGCGAT  CCCACAGCCTGCGAC  CCGCTTGAGGTCCACAT (SEQ ID NO: 4562) (SEQ ID NO: 4563) A (SEQ ID NO: 4564) hCV25629888 C/G GCACCTTGCTGCTGTCT GCACCTTGCTGCTGTCT GCCCTGATCACTGCAAA G  C  AC (SEQ ID NO: 4565) (SEQ ID NO: 4566) (SEQ ID NO: 4567) hCV25630686 C/T AGGTTGTACCTGTAGCA TAGGTTGTACCTGTAGC TGGGCTCCTCAGAGAAA CTAAGAC  ACTAAGAT  ATAT  (SEQ ID NO: 4568) (SEQ ID NO: 4569) (SEQ ID NO: 4570) hCV25631989 C/T AAGATAAGCCTGTCACT AAGATAAGCCTGTCACT CAAGCCAGCCTAATAAA GGTC  GGTT  CATAA  (SEQ ID NO: 4571) (SEQ ID NO: 4572) (SEQ ID NO: 4573) hCV25636622 C/T TCTGTAGTCAACAGGAG TCTGTAGTCAACAGGAG GCTGGGTTTTGGTGAAG AAGAGAC  AAGAGAT  TT  (SEQ ID NO: 4574) (SEQ ID NO: 4575) (SEQ ID NO: 4576) hCV25637309 A/T GGCCACTTTGCCTGAAT GGCCACTTTGCCTGAAT CGAAATGTTCATTTTTA A  T  AAGTCAGA  (SEQ ID NO: 4577) (SEQ ID NO: 4578) (SEQ ID NO: 4579) hCV25640504 C/T CCAAGATCTTCAGCAAC ACCAAGATCTTCAGCAA TGCAACCTCCACACAAT G  CA  CT  (SEQ ID NO: 4580) (SEQ ID NO: 4581) (SEQ ID NO: 4582) hCV25640504 C/T CTAAGGTCTTCAGCAAT CTAAGGTCTTCAGCAAT TGCAACCTCCACACAAT G  A  CT  (SEQ ID NO: 5415) (SEQ ID NO: 5416) (SEQ ID NO: 4582) hCV25642473 C/T CCACATAGATTCCTAAG ACCACATAGATTCCTAA CAAACACCATGGTTTTT AACG  GAACA  CTTT  (SEQ ID NO: 4583) (SEQ ID NO: 4584) (SEQ ID NO: 4585) hCV25643756 C/T CACTGCCATGCTCG  ACACTGCCATGCTCA  GCTGGCGCAGGAAGTAG  (SEQ ID NO: 4586) (SEQ ID NO: 4587) (SEQ ID NO: 4588) hCV25644901 A/G CAGACCTGCAGCTTCA  AGACCTGCAGCTTCG  TGTAACCCATCAACTCT (SEQ ID NO: 4589) (SEQ ID NO: 4590) GTTTATC  (SEQ ID NO: 4591) hCV25651076 A/G GATGCTGGCAAAGAACA  ATGCTGGCAAAGAACG  CAATCATCCACCTTTGT (SEQ ID NO: 4592) (SEQ ID NO: 4593) CTGT  (SEQ ID NO: 4594) hCV25651174 A/G CGCTGCAGGGTCAT  CGCTGCAGGGTCAC  CCTCCCCGCAGAGAATT (SEQ ID NO: 4595) (SEQ ID NO: 4596) A  (SEQ ID NO: 4597) hCV25652744 C/A AATGGTCCAGTTCCCTC CAATGGTCCAGTTCCCT TGAAGTGTGAATGATGC TC  CTA  TGATA  (SEQ ID NO: 4598) (SEQ ID NO: 4599) (SEQ ID NO: 4600) hCV25742059 A/G CTGCCTCTTCTGCATTA TGCCTCTTCTGCATTAG CCTTCACTGCCTGTTTC GA  G  TCT  (SEQ ID NO: 4601) (SEQ ID NO: 4602) (SEQ ID NO: 4603) hCV25745415 G/T TGACAGAGAATACTGGA CTGACAGAGAATACTGG CCATCTTGGCCATGTTT AGATATG  AAGATATT  AAT  (SEQ ID NO: 4604) (SEQ ID NO: 4605) (SEQ ID NO: 4606) hCV25749177 G/A CAGTGCTGGAACCTGTA CAGTGCTGGAACCTGTA TGGAGTCAAAGGTTAAA AGTC  AGTT  ACTCA  (SEQ ID NO: 4607) (SEQ ID NO: 4608) (SEQ ID NO: 4609) hCV25753038 T/C GGAGCCACCTATGTTCT GAGCCACCTATGTTCTC TCCCTCTTTGCTCATTC CTACT  TACC  ATC  (SEQ ID NO: 4610) (SEQ ID NO: 4611) (SEQ ID NO: 4612) hCV25767229 C/T GTGTGGCAATGAAGTCC AGTGTGGCAATGAAGTC GCAGTGCTCGTTACATG C  CT  AAAGATC  (SEQ ID NO: 4613) (SEQ ID NO: 4614) (SEQ ID NO: 4615) hCV25767417 A/G AGCCCCTTGTCTTCCAT  AGCCCCTTGTCTTCCAC  AAAGCAGTTCGACAAAA (SEQ ID NO: 4616) (SEQ ID NO: 4617) TCTTA  (SEQ ID NO: 4618) hCV25770061 A/C CCAAGCGACAGTCATAG CAAGCGACAGTCATAGT GTGCTGAATGTTTGCTC TCT  CG  TGTGTATCTAC  (SEQ ID NO: 4619) (SEQ ID NO: 4620) (SEQ ID NO: 4621) hCV25922320 A/G CTCGCAGCGGTCAGT  TCGCAGCGGTCAGC  GCTGGCGGGAATTTCT (SEQ ID NO: 4622) (SEQ ID NO: 4623) (SEQ ID NO: 4624) hCV25922440 C/T CGAACTCTTCAAGGTGG CCGAACTCTTCAAGGTG CCATGCATGCTTCAGGT TTG  GTTA  AAG (SEQ ID NO: 4625) (SEQ ID NO: 4626) (SEQ ID NO: 4627) hCV25922816 A/G TGGCACTCAGGGCAT  TGGCACTCAGGGCAC  CCAAAGAGGACTGACAA (SEQ ID NO: 4628) (SEQ ID NO: 4629) CTGTA (SEQ ID NO: 4630) hCV25924894 A/G GGGAAGTTCTTTCTTGT GGGAAGTTCTTTCTTGT TGCTGTCTTTGCCTCAC ATATTCAA  ATATTCAG  TAAT (SEQ ID NO: 4631) (SEQ ID NO: 4632) (SEQ ID NO: 4633) hCV25925481 A/G AATCAGCATTTTTGTCA ATCAGCATTTTTGTCAA GGCTTGTGACCTCATTG AAGA  AGG  TTT (SEQ ID NO: 4634) (SEQ ID NO: 4635) (SEQ ID NO: 4636) hCV25925974 G/C AAAGCAAAGGCACAGAG AAAGCAAAGGCACAGAG TGCCGTGCTGAGTTAAT AG  AC  G (SEQ ID NO: 4637) (SEQ ID NO: 4638) (SEQ ID NO: 4639) hCV25926178 C/G GCTTTATCAGAGACTCT GCTTTATCAGAGACTCT CCAAGGCCACGGATATC GAAGC  GAAGG  (SEQ ID NO: 4642) (SEQ ID NO: 4640) (SEQ ID NO: 4641) hCV2592654 A/C CAGTAAGCTGGAGAGTG AGTAAGCTGGAGAGTGG TGGGAGGTGGATAAGGC GA  C  AGATAAG (SEQ ID NO: 4643) (SEQ ID NO: 4644) (SEQ ID NO: 4645) hCV2592662 A/G GTTTGTGGGTTTTGTGG TTTGTGGGTTTTGTGGG CAGAGCAGCTTTCAAAC GA  G  TTTCTGAA (SEQ ID NO: 4646) (SEQ ID NO: 4647) (SEQ ID NO: 4648) hCV25926643 G/A CCTGGTTAGCTTTACCT CCCTGGTTAGCTTTACC CCCTTGCCATCCACACT TACG  TTACA  (SEQ ID NO: 4651) (SEQ ID NO: 4649) (SEQ ID NO: 4650) hCV25926771 C/T GGCCTTGGTCTCGC  TGGCCTTGGTCTCGT  TGCAGATCAGCTTGAAG (SEQ ID NO: 4652) (SEQ ID NO: 4653) AACTA (SEQ ID NO: 4654) hCV2592715 A/T CTGACCTTTCCTTTATT TGACCTTTCCTTTATTA GTGCCGCTGTTTCCTCA AAGCATCTATA  AGCATCTATT  TGT (SEQ ID NO: 4655) (SEQ ID NO: 4656) (SEQ ID NO: 4657) hCV25927459 G/T GGCTGTTGCTCCTCTTA TGGCTGTTGCTCCTCTT GGACCTGTCAATCTTGG TG  ATT  TCATCTAT (SEQ ID NO: 4658) (SEQ ID NO: 4659) (SEQ ID NO: 4660) hCV2592759 A/C TCCTCTCAGATAGTGTG CCTCTCAGATAGTGTGA CAACTGAGGCAAATACT AATACAATA  ATACAATC  GTGCTAACT (SEQ ID NO: 4661) (SEQ ID NO: 4662) (SEQ ID NO: 4663) hCV25928135 C/T TTTCACCGTATTAGCCA GTTTCACCGTATTAGCC CCCATAGTGGCCTCAAT GG  AGA AGT (SEQ ID NO: 4664) (SEQ ID NO: 4665) (SEQ ID NO: 4666) hCV25928538 C/G TCCACTGTTTTTGAACG TCCACTGTTTTTGAACG TAATTGCAAGAATATTG C  G AAAGACA (SEQ ID NO: 4667) (SEQ ID NO: 4668) (SEQ ID NO: 4669) hCV25930271 C/T GAATCTCATGTTCAGGA CGAATCTCATGTTCAGG GCCATGGCCCATAAAAC  AATG  AAATA  (SEQ ID NO: 4672) (SEQ ID NO: 4670) (SEQ ID NO: 4671) hCV25932224 T/G AGCCACTAAGCTCAAAC GCCACTAAGCTCAAACT CCCTAAAACCAAAGACG TCTTT  CTTG  TATGT  (SEQ ID NO: 4673) (SEQ ID NO: 4674) (SEQ ID NO: 4675) hCV25941408 G/T CATGGAGTCAACTCTTG GCATGGAGTCAACTCTT GGCTGTGCTTTGTCTGA AGG  GAGT  TCT  (SEQ ID NO: 4676) (SEQ ID NO: 4677) (SEQ ID NO: 4678) hCV25942539 G/A GGATCCGACCGTTGAG  GGATCCGACCGTTGAA  TCATTTTGAACTCATTT (SEQ ID NO: 4679) (SEQ ID NO: 4680) TTTCTAGA  (SEQ ID NO: 4681) hCV25943180 T/C GGTGGTCTTCCAGTCCT GGTGGTCTTCCAGTCCT TTGCTCCCTGCGAGTAA T  C  G  (SEQ ID NO: 4682) (SEQ ID NO: 4683) (SEQ ID NO: 4684) hCV25965660 A/G GGCCTGGTGGAAGTGAT  GGCCTGGTGGAAGTGAC  AGTGTCAAGGTAATCTG (SEQ ID NO: 4685) (SEQ ID NO: 4686) GTTTTT  (SEQ ID NO: 4687) hCV25972680 A/G GCAGGCCTTTCTCAGAA GCAGGCCTTTCTCAGAA CAGGAAGAGAAGAAGTC T  C  ACTTGT  (SEQ ID NO: 4688) (SEQ ID NO: 4689) (SEQ ID NO: 4690) hCV25996298 G/T CAGAGGCTGCTCCGC  ACAGAGGCTGCTCCGA  GGGTTTGTGGGCTCTTC  (SEQ ID NO: 4691) (SEQ ID NO: 4692) (SEQ ID NO: 4693) hCV26000635 C/A TGCTGGAGCAATTGAGA CTGCTGGAGCAATTGAG TCTTCCCCTCGTTTCTT G  AT  TC  (SEQ ID NO: 4694) (SEQ ID NO: 4695) (SEQ ID NO: 4696) hCV260164 G/T ACAGGTCACTGGGATTG ACAGGTCACTGGGATTG CTGGACAGTGTTTGGAA G  T  GGTCATA  (SEQ ID NO: 4697) (SEQ ID NO: 4698) (SEQ ID NO: 4699) hCV2604332 G/T GCAAATCAAGTAAAAGA GCAAATCAAGTAAAAGA CTGCAGCAGCTAAATGT TCTGTTTC  TCTGTTTA  CA  (SEQ ID NO: 4700) (SEQ ID NO: 4701) (SEQ ID NO: 4702) hCV26294850 C/T GCCCAAGCGGAAGGTAC GCATACCTTGCCAGTAG GCAGCACGAACTGC  GACTTTCCGGCTGAAAG CGATGCGGCGGCTGAAA (SEQ ID NO: 4705) CCG  GCCA  (SEQ ID NO: 4703) (SEQ ID NO: 4704) hCV2632070 A/G GACTAAAGTTCTGAGCC ACTAAAGTTCTGAGCCA GCCCTTTGTTCCTCGGT AATCAA  ATCAG  TTAGAG  (SEQ ID NO: 4706) (SEQ ID NO: 4707) (SEQ ID NO: 4708) hCV2632498 C/G CAATTGAGGTCCAGGAG CAATTGAGGTCCAGGAG TGGTGCAAACAGCTCTT C  G  CT  (SEQ ID NO: 4709) (SEQ ID NO: 4710) (SEQ ID NO: 4711) hCV2632544 C/T ACTGACCCTTCACACAT GTAACTGACCCTTCACA TGAGCCATCGTGCCTAG TTAC  CATTTAT  CTA  (SEQ ID NO: 4712) (SEQ ID NO: 4713) (SEQ ID NO: 4714) hCV2633049 G/T CTTCTAGGCTCTGTGGT CTTCTAGGCTCTGTGGT CCACGTGCCCATGAAG  CC  CA  (SEQ ID NO: 4717) (SEQ ID NO: 4715) (SEQ ID NO: 4716) hCV2658421 A/C CTCTCTTTCAGCATCTT CTCTCTTTCAGCATCTT TGCAGAAGAAAGAAACT GTAAAT  GTAAAG  TTATCAC  (SEQ ID NO: 4718) (SEQ ID NO: 4719) (SEQ ID NO: 4720) hCV26660340 C/G TGTGTCCAAAGGGACCA TGTGTCCAAAGGGACCA GACCCCATTTTCCTGGA C  G  CCATTAAG  (SEQ ID NO: 4721) (SEQ ID NO: 4722) (SEQ ID NO: 4723) hCV26683367 C/G CCTATTAAGATGAGAAC CCTATTAAGATGAGAAC GGAGGTGGAAGAGCATT CTCAACAC  CTCAACAG  GAAACT  (SEQ ID NO: 4724) (SEQ ID NO: 4725) (SEQ ID NO: 4726) hCV26683368 C/T TGTAAAATGCCTGTCAC GTGTAAAATGCCTGTCA CGATGACATTCTTGGTC GG  CGA  TGTACACT  (SEQ ID NO: 4727) (SEQ ID NO: 4728) (SEQ ID NO: 4729) hCV2680532 A/C GGGCCTCACCTTGGT  GGGCCTCACCTTGGG  GCCTCCCCAGATTGATG (SEQ ID NO: 4730) (SEQ ID NO: 4731) TCT  (SEQ ID NO: 4732) hCV26809148 A/G CATCATGGTGTTCTTGC ATCATGGTGTTCTTGCC CATTATCTGAAATGTTT CT  C  CATTGTAGA  (SEQ ID NO: 4733) (SEQ ID NO: 4734) (SEQ ID NO: 4735) hCV26898946 C/T TGGGTGGCAGTCCC  GTGGGTGGCAGTCCT  GGGGACAGGTATGCATG (SEQ ID NO: 4736) (SEQ ID NO: 4737) TCAT  (SEQ ID NO: 4738) hCV27157435 C/T GGAACTTAATTGCTTGA GGAACTTAATTGCTTGA GACACCACCGTCCTACA TACTATCAC  TACTATCAT  CTG  (SEQ ID NO: 4739) (SEQ ID NO: 4740) (SEQ ID NO: 4741) hCV27157439 A/C GTAACTAACACTCAGAA GTAACTAACACTCAGAA GTTGAGGCTGCAGTGAG GTACATTTT  GTACATTTG  CTATAAT  (SEQ ID NO: 4742) (SEQ ID NO: 4743) (SEQ ID NO: 4744) hCV2741051 C/T GCAGCCAGTTTCTCCC   TGCAGCCAGTTTCTCCT  CATGAAATGCTTCCAGG (SEQ ID NO: 4745) (SEQ ID NO: 4746) TATT  (SEQ ID NO: 4747) hCV2741083 C/T GTTCCAACCAGAAGAGA GGTTCCAACCAGAAGAG CTTGCCCCCAACAGTTA ATG  AATA  G  (SEQ ID NO: 4748) (SEQ ID NO: 4749) (SEQ ID NO: 4750) hCV27422538 C/G GCAATCTCTCCTTCCTC GCAATCTCTCCTTCCTC ACACACACACCTCCACA TCC  TCG  AATACTAA  (SEQ ID NO: 4751) (SEQ ID NO: 4752) (SEQ ID NO: 4753) hCV27457080 C/T AAATAGGTCGTTCTGAC AAATAGGTCGTTCTGAC CCCACTCCACCATCTGT ATAAAAG  ATAAAAA  ATAG  (SEQ ID NO: 4754) (SEQ ID NO: 4755) (SEQ ID NO: 4756) hCV27462774 A/G AAGATCATGATTTATCT AGATCATGATTTATCTT GGTGGTCAGCACATGAC TGGTTCCTA  GGTTCCTG  TTCT  (SEQ ID NO: 4757) (SEQ ID NO: 4758) (SEQ ID NO: 4759) hCV27480853 C/T CCTGTTAGGTGTGTTGC CCTGTTAGGTGTGTTGC GCTTACGCCATTTTCTG TTTAAC  TTTAAT  TCGGTATTT  (SEQ ID NO: 4760) (SEQ ID NO: 4761) (SEQ ID NO: 4762) hCV2762168 C/T CCCCATGGTTTGTTGTT CCCCATGGTTTGTTGTT CGACTTCAGTGACCACA GC  GT  CATAACA  (SEQ ID NO: 4763) (SEQ ID NO: 4764) (SEQ ID NO: 4765) hCV2769554 A/G TCCGTTGTTCTCAGGGA TCCGTTGTTCTCAGGGA GGTTCCTGGAGGCATGT T  C  C  (SEQ ID NO: 4766) (SEQ ID NO: 4767) (SEQ ID NO: 4768) hCV2781953 G/T ACATTGCGGTTATTGCT ACATTGCGGTTATTGCT CACCTGCCTCTCTCAAA AGTG  AGTT  GAATAGC  (SEQ ID NO: 4769) (SEQ ID NO: 4770) (SEQ ID NO: 4771) hCV27884601 C/T GGAATATTTGGGTTTGT GGAATATTTGGGTTTGT CTGGGACTGTCTATTTT TTCACC  TTCACT  CTTTCATTCAACC  (SEQ ID NO: 4772) (SEQ ID NO: 4773) (SEQ ID NO: 4774) hCV27958354 C/T GCTATGAGGAGAACACA GCTATGAGGAGAACACA CATTCCCTCTGCCCCTT AGAATATAC  AGAATATAT  CTTAGATA  (SEQ ID NO: 4775) (SEQ ID NO: 4776) (SEQ ID NO: 4777) hCV27970553 C/T ACCTAAACTTTGGTATC CACCTAAACTTTGGTAT CTCACCCGCTGATATTT ACCG  CACCA  GTTTAACCT  (SEQ ID NO: 4778) (SEQ ID NO: 4779) (SEQ ID NO: 4780) hCV28008078 C/T CTGTCACAAGCAACAGA TCTGTCACAAGCAACAG CGAGGAGGAGATAACTG AAG  AAAA  GATGTGT  (SEQ ID NO: 4781) (SEQ ID NO: 4782) (SEQ ID NO: 4783) hCV28023091 C/T TTCAGTTCTTTGCAGTA TTCAGTTCTTTGCAGTA CATTTGTCTGAGGGTTC ATAAACAG  ATAAACAA  ACTTGTTGA  (SEQ ID NO: 4784) (SEQ ID NO: 4785) (SEQ ID NO: 4786) hCV2822674 A/G GATGCTGGGTGGATGTT  GATGCTGGGTGGATGTC  TGTGGCCCTGAGAATGT (SEQ ID NO: 4787) (SEQ ID NO: 4788) AC  (SEQ ID NO: 4789) hCV282793 C/T ATCTATTCACAAACACA ATCTATTCACAAACACA GAGACACCCAAGCAAAC TGAACAAG  TGAACAAA  TGAACTTAC  (SEQ ID NO: 4790) (SEQ ID NO: 4791) (SEQ ID NO: 4792) hCV2829795 A/G GTTTCTCTCCAGTATGA GTTTCTCTCCAGTATGA AATTCATTCTGGAGAGA ATTCTTT  ATTCTTC  AATCTTAC  (SEQ ID NO: 4793) (SEQ ID NO: 4794) (SEQ ID NO: 4795) hCV28960526 A/T TGAAGGCACCTGTCATC TGAAGGCACCTGTCATC CTCCTGGTGGGCCTTTT AT  AA  GAAATA  (SEQ ID NO: 4796) (SEQ ID NO: 4797) (SEQ ID NO: 4798) hCV28974083 A/G TTCACTTCAAGCTTCCA TCACTTCAAGCTTCCAT CCTCCTCTTCTCATCAA TAGTTAT  AGTTAC  TCCCAAATTAGT  (SEQ ID NO: 4799) (SEQ ID NO: 4800) (SEQ ID NO: 4801) hCV28993059 A/G GAATGAGTAAGGGAAGA GAATGAGTAAGGGAAGA GCTGAATTGTCTGACGG GGAAAA  GGAAAG  AATCT  (SEQ ID NO: 4802) (SEQ ID NO: 4803) (SEQ ID NO: 4804) hCV29011391 A/G GCTCGGAAAAGCCAAGA GCTCGGAAAAGCCAAGA GATCCAGATTTTGTCAA AA  AG  AGCCACTAGA  (SEQ ID NO: 4805) (SEQ ID NO: 4806) (SEQ ID NO: 4807) hCV29033518 A/T GCATTATACATGTGCAG GCATTATACATGTGCAG CCACCATGGCTGTGTCT TCACATT  TCACATA  TGT  (SEQ ID NO: 4808) (SEQ ID NO: 4809) (SEQ ID NO: 4810) hCV29135108 A/C GGAGTGCTTTTATGGCA GGAGTGCTTTTATGGCA GCTGATAGTGCAAGTTA AAA  AAC  GCAACATAGT  (SEQ ID NO: 4811) (SEQ ID NO: 4812) (SEQ ID NO: 4813) hCV29195255 A/C TCCAGCAATTCCACTTC CCAGCAATTCCACTTCC AGAACTAGCAAAGCACC CA  C  TCTGTAGAA  (SEQ ID NO: 4814) (SEQ ID NO: 4815) (SEQ ID NO: 4816) hCV29195260 A/G CATTATCTAGTTTCTTT CATTATCTAGTTTCTTT AGCATCTTCTGTGTCCA ACTTGTCTTCT  ACTTGTCTTCC  GCTAAGT  (SEQ ID NO: 4817) (SEQ ID NO: 4818) (SEQ ID NO: 4819) hCV2932115 C/T TGGACGTGGGCTTTTTC  TGGACGTGGGCTTTTTT  GCTGCAGCCCTTTTTCT (SEQ ID NO: 4820) (SEQ ID NO: 4821) C  (SEQ ID NO: 4822) hCV29322781 A/G AGATATCCACTACTCTT AGATATCCACTACTCTT CTTAAGCCAGTCCTGCA CTTCTCAA  CTTCTCAG  CAACTAG  (SEQ ID NO: 4823) (SEQ ID NO: 4824) (SEQ ID NO: 4825) hCV29368919 C/T GCTTCAAGAGGATAAAG GCTTCAAGAGGATAAAG GATATAACCTGTCACTA TAAAACAGAG  TAAAACAGAA  CACTGGACTGAA  (SEQ ID NO: 4826) (SEQ ID NO: 4827) (SEQ ID NO: 4828) hCV29480044 C/T GGTGGGCCTTTTGAAAT TGGTGGGCCTTTTGAAA CTTGAAGTGAAGGCACC AAAC  TAAAT  TGTCAT  (SEQ ID NO: 4829) (SEQ ID NO: 4830) (SEQ ID NO: 4831) hCV2948766 A/G ACAATAACCCTTCTAAT CAATAACCCTTCTAATT GTGTTGCTGAAATCATG TGCACA  GCACG  GAGTCTGAT  (SEQ ID NO: 4832) (SEQ ID NO: 4833) (SEQ ID NO: 4834) hCV2960489 A/G CCCACCATCCACTTCCT  CCCACCATCCACTTCCC  CTCCAGCGTTGGGGATG (SEQ ID NO: 4835) (SEQ ID NO: 4836) ATG  (SEQ ID NO: 4837) hCV2966448 A/G GTTAAACCTTCTTTATC GTTAAACCTTCTTTATC CGCTTCGCCTTGGGATA TCCTCCTT  TCCTCCTC  TG  (SEQ ID NO: 4838) (SEQ ID NO: 4839) (SEQ ID NO: 4840) hCV29684678 C/G CAGCTACACTTCAGTCT CAGCTACACTTCAGTCT GAGAAGGAGACTGGAGA ACTTAG  ACTTAC  CAGATATGAC  (SEQ ID NO: 4841) (SEQ ID NO: 4842) (SEQ ID NO: 4843) hCV29809835 A/C GTCTCGGAAGCAATGTT TCTCGGAAGCAATGTTC GCTTCTGCCACCCCTGT CTA  TC  AAAT  (SEQ ID NO: 4844) (SEQ ID NO: 4845) (SEQ ID NO: 4846) hCV29819064 C/T TCGCTTTGAAACACTCT CTCGCTTTGAAACACTC CTGTGGCTTCAGGCTTT GC  TGT  ACAGT  (SEQ ID NO: 4847) (SEQ ID NO: 4848) (SEQ ID NO: 4849) hCV2983035 A/G TTGGACCCTCACATGAA TTGGACCCTCACATGAA GCCATTTTCCACAATAA A  G  ATATTT  (SEQ ID NO: 4850) (SEQ ID NO: 4851) (SEQ ID NO: 4852) hCV2983036 C/G GCTGACTTTTTTGCTCT GCTGACTTTTTTGCTCT GCCATTTTCCACAATAA TTC  TTG  ATATTT  (SEQ ID NO: 4853) (SEQ ID NO: 4854) (SEQ ID NO: 4855) hCV2987229 C/T GGAGGGAGGCAACCAC  GGAGGGAGGCAACCAT  TGCCCGATAAACGTGAG (SEQ ID NO: 4856) (SEQ ID NO: 4857) GTAGAA  (SEQ ID NO: 4858) hCV2987250 C/G ACTGCTCCAAGATAGAG ACTGCTCCAAGATAGAG CAGCATTTGTGAGAGGA GTAC  GTAG  GCTGTTT  (SEQ ID NO: 4859) (SEQ ID NO: 4860) (SEQ ID NO: 4861) hCV29873524 C/T TCATCAAACCACTCAAG TTTCATCAAACCACTCA CACTCAAATGGAAGAGT CTAC  AGCTAT  CATTGGTGAAT  (SEQ ID NO: 4862) (SEQ ID NO: 4863) (SEQ ID NO: 4864) hCV2992252 T/C CCCTGTGATTGGCCAT  CCCTGTGATTGGCCAC  CCTGCTCGCTCTGTCAC  (SEQ ID NO: 4865) (SEQ ID NO: 4866) (SEQ ID NO: 4867) hCV29945430 G/T GAGCTCATGTGCATTAT AGAGCTCATGTGCATTA CCGCCTACTGACTACCT AAACG  TAAACT  GTCTA  (SEQ ID NO: 4868) (SEQ ID NO: 4869) (SEQ ID NO: 4870) hCV29952522 A/G ACTGGAAAGATGACACA CTGGAAAGATGACACAT GGGCTACACCCAAAGGC TCTACA  CTACG  TAAATC  (SEQ ID NO: 4871) (SEQ ID NO: 4872) (SEQ ID NO: 4873) hCV30136303 C/G TCACCCCACTCTGCTAT TCACCCCACTCTGCTAT CAAAGGCTGGGAAGGGT AG  AC  ATGTATATTG  (SEQ ID NO: 4874) (SEQ ID NO: 4875) (SEQ ID NO: 4876) hCV30233466 A/G GCGCCCGGATGGAAT  GCGCCCGGATGGAAC  ACGCCCACTCCAGTTAC (SEQ ID NO: 4877) (SEQ ID NO: 4878) TAAACA  (SEQ ID NO: 4879) hCV3026189 C/T CTTCTTGCCCTTCAGCT CTTCTTGCCCTTCAGCT CCCAGTTCTGAGATGTG C  T  TATGT  (SEQ ID NO: 4880) (SEQ ID NO: 4881) (SEQ ID NO: 4882) hCV30264691 G/T TTCTCCTGAAGAATTGT TTTCTCCTGAAGAATTG GAAGTTAGCCAATCTTG AAGCC  TAAGCA  TCATCTTTTCACT  (SEQ ID NO: 4883) (SEQ ID NO: 4884) (SEQ ID NO: 4885) hCV30287627 A/T AATGCAAAATGCAAACT CAATGCAAAATGCAAAC TGGAGTTGTCGTCCTGT GTCTAA  TGTCTAT  GGATAAT  (SEQ ID NO: 4886) (SEQ ID NO: 4887) (SEQ ID NO: 4888) hCV30454150 C/T TCTAGCAGATTTGTATC TAATCTAGCAGATTTGT GCGACCCTCTCTGGTTA AGAACC  ATCAGAACT  AACA  (SEQ ID NO: 4889) (SEQ ID NO: 4890) (SEQ ID NO: 4891) hCV30467730 C/T CTCTACTGTTTAGAATC CTCTACTGTTTAGAATC CCAGCGGTAATTGGAGC GTTTTCAAC  GTTTTCAAT  AATCTTA  (SEQ ID NO: 4892) (SEQ ID NO: 4893) (SEQ ID NO: 4894) hCV30534667 A/G AGAACAACTCAAAGGTG AGAACAACTCAAAGGTG ACATGACCTGTTCTAAC CAAA  CAAG  TGGGAGTTATG  (SEQ ID NO: 4895) (SEQ ID NO: 4896) (SEQ ID NO: 4897) hCV30574599 C/T CCATGCACACTTTAATG TCCATGCACACTTTAAT CCCAAACACAACAGGCT TGTAC  GTGTAT  AGAACAAAT  (SEQ ID NO: 4898) (SEQ ID NO: 4899) (SEQ ID NO: 4900) hCV30586985 A/G TCGGTGATTGGTACAAG CGGTGATTGGTACAAGA GCTGGAATGGTACTCCT AGTAA  GTAG  GAGTATGT  (SEQ ID NO: 4901) (SEQ ID NO: 4902) (SEQ ID NO: 4903) hCV30606396 C/T ACATTTGCTCATTCTGT CACATTTGCTCATTCTG CAAGAGATCTGGAGGTG ACTCC  TACTCT  GGGATTAT  (SEQ ID NO: 4904) (SEQ ID NO: 4905) (SEQ ID NO: 4906) hCV3068176 A/G TACCACAGCTTGCTCAC TACCACAGCTTGCTCAC TTTCCCCCATTTTTCAG AT  AC  TT  (SEQ ID NO: 4907) (SEQ ID NO: 4908) (SEQ ID NO: 4909) hCV30764105 C/G GGCCCTGAACCTTTCAG  GGCCCTGAACCTTTCAC  CGAATTAGTAAGTTACC (SEQ ID NO: 4910) (SEQ ID NO: 4911) AGTGACATCAGC  (SEQ ID NO: 4912) hCV3086932 G/T TGTATCGAGAGAGAAAG TTGTATCGAGAGAGAAA CTCCACCAAATACCCTC ATAGTTTG  GATAGTTTT  ATCTGTTCT  (SEQ ID NO: 4913) (SEQ ID NO: 4914) (SEQ ID NO: 4915) hCV3086948 C/T CTGGCATATTTTGAAGT CTCTGGCATATTTTGAA CTCTGGAAAGGGAAATG ATTCTCTG  GTATTCTCTA  TCACTCTA  (SEQ ID NO: 4916) (SEQ ID NO: 4917) (SEQ ID NO: 4918) hCV3086950 A/G CTCCTTGCCTCAAATGA TCCTTGCCTCAAATGAT TTCAGTCATACTCATGG TTTCT  TTCC  TCCAAATCTCATT  (SEQ ID NO: 4919) (SEQ ID NO: 4920) (SEQ ID NO: 4921) hCV3086961 A/C AAGCATCCAGAGCCTCT AGCATCCAGAGCCTCTT GCTGTCCACCTGTCACT TAT  AG  TTCATAAT  (SEQ ID NO: 4922) (SEQ ID NO: 4923) (SEQ ID NO: 4924) hCV3086983 C/T GCATAACTAAACTATAG GCATAACTAAACTATAG GACGTGGCCAGCCATCT TGTACAGACAC  TGTACAGACAT  TC  (SEQ ID NO: 4925) (SEQ ID NO: 4926) (SEQ ID NO: 4927) hCV3087000 A/G GAGCATAGAAACAATTT AGCATAGAAACAATTTT AGTGTGTGGTTTCAGCA TGTTCCAT  GTTCCAC  GTACTAGATT  (SEQ ID NO: 4928) (SEQ ID NO: 4929) (SEQ ID NO: 4930) hCV3087003 C/G CCTGGGCAAGATGGTAA CCTGGGCAAGATGGTAA CTGGGCTCAGGCAATCC AAC  AAG  TA  (SEQ ID NO: 4931) (SEQ ID NO: 4932) (SEQ ID NO: 4933) hCV3087008 A/C CAGAGTCCTTCAGTAAA CAGAGTCCTTCAGTAAA CCACCTTCTTTCAACCC CTTCTTT  CTTCTTG  AAATTTTCTC  (SEQ ID NO: 4934) (SEQ ID NO: 4935) (SEQ ID NO: 4936) hCV3087015 C/G ACAGCTTTTACTTACCT ACAGCTTTTACTTACCT AGCTGAGTGGGAGAGAA TTGATAGAG  TTGATAGAC  GAATACAC  (SEQ ID NO: 4937) (SEQ ID NO: 4938) (SEQ ID NO: 4939) hCV3087016 A/C AGCACTCCATAACTTTA GCACTCCATAACTTTAC GACTACACACAAGATCA CCCT  CCG  ACTAATAGAAATACTGC (SEQ ID NO: 4940) (SEQ ID NO: 4941) (SEQ ID NO: 4942) hCV3111721 C/T ACCGTTGTCCTCCC  GACCGTTGTCCTCCT  GCCTCTAGCACGATGGA (SEQ ID NO: 4943) (SEQ ID NO: 4944) TAG  (SEQ ID NO: 4945) hCV3111822 C/T AAACCTTCCTACACAGA AAACCTTCCTACACAGA CTGGTGGTGGTGAGAAG ACTTC  ACTTT  AACAT  (SEQ ID NO: 4946) (SEQ ID NO: 4947) (SEQ ID NO: 4948) hCV31145250 A/C CTGAGCCACCTTATCTG TGAGCCACCTTATCTGT CACAGGGTTGTTAACCT TTAAAA  TAAAC  TGGTTTAG  (SEQ ID NO: 4949) (SEQ ID NO: 4950) (SEQ ID NO: 4951) hCV31161091 A/G ACACCTGCTGACTATCC CACCTGCTGACTATCCA CATCGTGATCCTGCCAA AAT  AC  GTAGAGA  (SEQ ID NO: 4952) (SEQ ID NO: 4953) (SEQ ID NO: 4954) hCV31237961 A/C GGCGAAGACAAAATTAT GGCGAAGACAAAATTAT CCAGGAAGCTCAGGCAA ATTTCAACT  ATTTCAACG  ATTTGA  (SEQ ID NO: 4955) (SEQ ID NO: 4956) (SEQ ID NO: 4957) hCV3135085 G/T CTGGAAATGGTTATGGG TACTGGAAATGGTTATG TTTATAGGCGTGAAACT C  GGA  AATTCTC  (SEQ ID NO: 4958) (SEQ ID NO: 4959) (SEQ ID NO: 4960) hCV31356445 G/T GCCTGTGGTTGTCTTCC GCCTGTGGTTGTCTTCC ACTTCCTCAGGTCTGCT C  A  GTGT  (SEQ ID NO: 4961) (SEQ ID NO: 4962) (SEQ ID NO: 4963) hCV31466171 A/G CTCCAATCCCACATTTC TCCAATCCCACATTTCC CCATGACTCTTCAGAAC CA  G CTGTTTGT  (SEQ ID NO: 4964) (SEQ ID NO: 4965) (SEQ ID NO: 4966) hCV3152623 A/C CTGCAGAAACGATCAGT TGCAGAAACGATCAGTG TGCTTCTGTCATTCTTT GT  G  CTGAT  (SEQ ID NO: 4967) (SEQ ID NO: 4968) (SEQ ID NO: 4969) hCV31528409 A/G TGCCTGGACTGTGTTCT TGCCTGGACTGTGTTCT GAGGCAGAGGTTTCAGT T  C  GAGTAGA  (SEQ ID NO: 4970) (SEQ ID NO: 4971) (SEQ ID NO: 4972) hCV3168675 A/G TCTCCCACTGTGTTCCT CTCCCACTGTGTTCCTG  TGCCAGGGATTGGTTGC A  (SEQ ID NO: 4974) TTAATAC  (SEQ ID NO: 4973) (SEQ ID NO: 4975) hCV3170445 C/T GCTGCAAAAATGAACAA GCTGCAAAAATGAACAA GAATGCATAGCTGATCT CAC  CAT  CAAGA  (SEQ ID NO: 4976) (SEQ ID NO: 4977) (SEQ ID NO: 4978) hCV3170459 C/T GACTGTCCTGATTGGAA TGACTGTCCTGATTGGA GGCATTTTGGTATCATT TCC  ATCT  TTGTTA  (SEQ ID NO: 4979) (SEQ ID NO: 4980) (SEQ ID NO: 4981) hCV3179059 G/T CATCCTCGTGGGAAGTG  CATCCTCGTGGGAAGTT  CCAACCTCTGCTCTCTG (SEQ ID NO: 4982) (SEQ ID NO: 4983) ATAAT  (SEQ ID NO: 4984) hCV3180404 A/G CAGCAGAGCAGCCTTAA CAGCAGAGCAGCCTTAG  TGATGCTGGAAGCACTT (SEQ ID NO: 4985) (SEQ ID NO: 4986) CT  (SEQ ID NO: 4987) hCV3181997 A/G TGGATCCTGACTTTGTG TGGATCCTGACTTTGTG GGAATCTGAAGGAGACA AAAT AAAC  TTTTTAC  (SEQ ID NO: 4988) (SEQ ID NO: 4989) (SEQ ID NO: 4990) hCV3187716 A/C CCTTCAATTCTGAAAAG CCTTCAATTCTGAAAAG TTTGAGGTTGAGTGACA TAGCTAAT TAGCTAAG  TGTTC  (SEQ ID NO: 4991) (SEQ ID NO: 4992) (SEQ ID NO: 4993) hCV31954792 A/C CCGGAGGCTAGATTATT CGGAGGCTAGATTATTA ATCCCATTCCCTCCCTT ACCT CCG  CACATAA  (SEQ ID NO: 4994) (SEQ ID NO: 4995) (SEQ ID NO: 4996) hCV3201490 A/G GCAGTCCTGCCGTACT GCAGTCCTGCCGTACC  ACTGCTCAACTACCTGG (SEQ ID NO: 4997) (SEQ ID NO: 4998) TGGATAAG  (SEQ ID NO: 4999) hCV32055474 C/G GAACAGTTCAGATTTAC AGAACAGTTCAGATTTA CCACTGTTAACATTTGT AAGTGC CAAGTGG  TGTATGGTCAGT  (SEQ ID NO: 5000) (SEQ ID NO: 5001) (SEQ ID NO: 5002) hCV32055477 A/G GAGTGCTAACAGAGTAA GAGTGCTAACAGAGTAA AAGGTCTCACCTGGTAT TTACCAA TTACCAG  GCTGTATTTT  (SEQ ID NO: 5003) (SEQ ID NO: 5004) (SEQ ID NO: 5005) hCV32055527 A/C ACACCCCAACGTCATCA ACACCCCAACGTCATCC  AAGCCTTGGAAAGCGAA (SEQ ID NO: 5006) (SEQ ID NO: 5007) ACTGT  (SEQ ID NO: 5008) hCV32055581 A/G GTGAGACAGCAAACACT TGAGACAGCAAACACTA TTCCCGAAGAGCTGGAA ATACA TACG  TTACAGT  (SEQ ID NO: 5009) (SEQ ID NO: 5010) (SEQ ID NO: 5011) hCV32055595 C/T ACCATCTACTATGAGCC AAACCATCTACTATGAG GTCTGTTGCCCATGGAT TCC CCTCT  GATTACA  (SEQ ID NO: 5012) (SEQ ID NO: 5013) (SEQ ID NO: 5014) hCV32055596 A/G GAAACTAGTTCTGTCTT GAAACTAGTTCTGTCTT GGGTCACAGACTTAGCC CTAGCAT  CTAGCAC  AGTGATA  (SEQ ID NO: 5015) (SEQ ID NO: 5016) (SEQ ID NO: 5017) hCV32055625 C/T CTTCAGACAAGCTGTCC ATCTTCAGACAAGCTGT GAAACCTAATTGGCCCA TG  CCTA  GGTCATC  (SEQ ID NO: 5018) (SEQ ID NO: 5019) (SEQ ID NO: 5020) hCV32055654 A/G TGATGCACAAGAGTGTT TGATGCACAAGAGTGTT GAGCTTGGATTAGGCAA TACTTT  TACTTC  TGGTTTCT  (SEQ ID NO: 5021) (SEQ ID NO: 5022) (SEQ ID NO: 5023) hCV3215409 A/G GTGGCTCATTACCAATC GTGGCTCATTACCAATC GGGCTCCATCAACATCA TCTT  TCTC  C  (SEQ ID NO: 5024) (SEQ ID NO: 5025) (SEQ ID NO: 5026) hCV3219460 G/T GCAGGCCCCAGATGAG  GCAGGCCCCAGATGAT  CCATCCCACCCAGTCAA  (SEQ ID NO: 5027) (SEQ ID NO: 5028) (SEQ ID NO: 5029) hCV323070 A/G GCCCAGAAAGATGAGTT GCCCAGAAAGATGAGTT TGTCCCTTTTTCAGAGA CA  CG  CATAGAT  (SEQ ID NO: 5030) (SEQ ID NO: 5031) (SEQ ID NO: 5032) hCV323071 A/G AAACCAGGATATCAGAA ACCAGGATATCAGAACA GGTCTTAGGAATTATCT CATTTTA  TTTTG  GACATCTT  (SEQ ID NO: 5033) (SEQ ID NO: 5034) (SEQ ID NO: 5035) hCV3242919 A/C GTGAGTTTTCGTCCCAC TGAGTTTTCGTCCCACG  AAGTGGCCTTTTCTAAG T  (SEQ ID NO: 5037) GGGTAGAA  (SEQ ID NO: 5036) (SEQ ID NO: 5038) hCV3242952 A/G GCTATGTGGTTTGAAAT GCTATGTGGTTTGAAAT GGAGCACTGGGTCCTAG TGTTCT  TGTTCC  ATGT  (SEQ ID NO: 5039) (SEQ ID NO: 5040) (SEQ ID NO: 5041) hCV3259235 A/G TCCTCTCCTTGTATCTT TCCTCTCCTTGTATCTT GAGGTAATCAGGTCATG CACAT  CACAC  AGGGTATAGT  (SEQ ID NO: 5042) (SEQ ID NO: 5043) (SEQ ID NO: 5044) hCV3275199 A/G CCATGCAACCAAACCAT  CCATGCAACCAAACCAC  CCTCTCATCCCTCTCAT (SEQ ID NO: 5045) (SEQ ID NO: 5046) CTTT  (SEQ ID NO: 5047) hCV334752 C/T CTGTTCCAATATCTCTT TCTGTTCCAATATCTCT GCAAACCATAGCACGCT TCCCC  TTCCCT  TATACA  (SEQ ID NO: 5048) (SEQ ID NO: 5049) (SEQ ID NO: 5050) hCV341736 C/T GTCTGGTGACATAAGGT GTCTGGTGACATAAGGT AGGTGAATTACATAGGA ATTAAATTAAATC  ATTAAATTAAATT  CCCTTTGTGT  (SEQ ID NO: 5051) (SEQ ID NO: 5052) (SEQ ID NO: 5053) hCV342590 C/T AGACAAATTCTCTCATG AGACAAATTCTCTCATG TGTTTTTCCAGGAAAAA TCCAC  TCCAT  GATATTC  (SEQ ID NO: 5054) (SEQ ID NO: 5055) (SEQ ID NO: 5056) hCV361088 A/G CGACTTTCTAGAGGAAA CGACTTTCTAGAGGAAA CCCAGCAGTCCCGTTGC TTTAGGT  TTTAGGC  TTT  (SEQ ID NO: 5057) (SEQ ID NO: 5058) (SEQ ID NO: 5059) hCV370782 C/T TCTACCCAGGTACTTAT TTTCTACCCAGGTACTT GGATTCACTGTGAAAGA CATCC  ATCATCT  ACAGTAT  (SEQ ID NO: 5060) (SEQ ID NO: 5061) (SEQ ID NO: 5062) hCV435368 T/C GAGGTCTTGAAATACAG GAGGTCTTGAAATACAG TCTTGAGAGGTGTGATC GGATT  GGATC  ATAACTT  (SEQ ID NO: 5063) (SEQ ID NO: 5064) (SEQ ID NO: 5065) hCV461035 C/T TGTTTCCCTTATGACAA CTGTTTCCCTTATGACA AGGGTCGGTCAAACTCA CACG  ACACA  TGCTATAT  (SEQ ID NO: 5066) (SEQ ID NO: 5067) (SEQ ID NO: 5068) hCV472000 A/G AAGAATTCACACCCAGG AGAATTCACACCCAGGT CAACTCCTGAGTTCAAG TTTATT  TTATC  CAGTCTG  (SEQ ID NO: 5069) (SEQ ID NO: 5070) (SEQ ID NO: 5071) hCV487868 C/T GCCACAATTTGGAGTTA GCCACAATTTGGAGTTA CCAATCCAGCCCTCTTG CAGG  CAGA  TGTTTG  (SEQ ID NO: 5072) (SEQ ID NO: 5073) (SEQ ID NO: 5074) hCV491676 T/C GAATTGCAAGTGCTTGT GAATTGCAAGTGCTTGT CCGATTCCCCAGTAACA TTTAT  TTTAC  AC  (SEQ ID NO: 5075) (SEQ ID NO: 5076) (SEQ ID NO: 5077) hCV529178 C/T TGGGTTGGTGGGCAG  TGGGTTGGTGGGCAA  GTGGCAGCCAATCTGAG (SEQ ID NO: 5078) (SEQ ID NO: 5079) TACT  (SEQ ID NO: 5080) hCV529706 C/G GCGAGGACGAAGGGG  GCGAGGACGAAGGGC  GGAGGATGAATGGACAG (SEQ ID NO: 5081) (SEQ ID NO: 5082) ACAA  (SEQ ID NO: 5083) hCV529710 C/G CCGACCCGAACTAAAGG  CCGACCCGAACTAAAGC  CGCGTTCCCCATGTC  (SEQ ID NO: 5084) (SEQ ID NO: 5085) (SEQ ID NO: 5086) hCV537525 A/C TCATAGATCCCTACTTG TCATAGATCCCTACTTG CGCACTGTTCCCTTATC TGCTAA  TGCTAC  GAGATT  (SEQ ID NO: 5087) (SEQ ID NO: 5088) (SEQ ID NO: 5089) hCV5478 C/T CGGCTTTCTGGTGGG  ACGGCTTTCTGGTGGA  GGCTCCGAGGACGAGA  (SEQ ID NO: 5090) (SEQ ID NO: 5091) (SEQ ID NO: 5092) hCV549926 C/T ACCATGGTCACCCTGG  CACCATGGTCACCCTGA  GGACTGAAAGCAATGTG (SEQ ID NO: 5093) (SEQ ID NO: 5094) AGAG  (SEQ ID NO: 5095) hCV561574 A/G GCCATTTATGTAGCCAA GCCATTTATGTAGCCAA GCAGGTTATAAAGTGTG ACTGA  ACTGG  AGAGATCTGAGTA  (SEQ ID NO: 5096) (SEQ ID NO: 5097) (SEQ ID NO: 5098) hCV594695 A/T ATATCGTGGGTGAGTTC TCGTGGGTGAGTTCATT GGGTGCTGCTGATGAAA ATTTA  TT  TAC  (SEQ ID NO: 5099) (SEQ ID NO: 5100) (SEQ ID NO: 5101) hCV597227 C/T TTTCTGCAAACTAATTG CTTTCTGCAAACTAATT GTCAAGTCCTTTCGGAA ACAGAAC  GACAGAAT  ATGAGACA  (SEQ ID NO: 5102) (SEQ ID NO: 5103) (SEQ ID NO: 5104) hCV598677 G/T CCAAGCTGAAAGGCAAG  CCAAGCTGAAAGGCAAT  CAGCCAGGGTGGAGAGT  (SEQ ID NO: 5105) (SEQ ID NO: 5106) (SEQ ID NO: 5107) hCV601946 A/G CTCCATTCTCTTACCCC TCCATTCTCTTACCCCT TTGGGGATGGACTCAAG TCTTAT  CTTAC  ATGTGT  (SEQ ID NO: 5108) (SEQ ID NO: 5109) (SEQ ID NO: 5110) hCV601961 A/G CCATTAATTATGAGTGC CCATTAATTATGAGTGC CCAACCACTCTGGTAGA TCTTACCTAAA  TCTTACCTAAG  CGTGTAA  (SEQ ID NO: 5111) (SEQ ID NO: 5112) (SEQ ID NO: 5113) hCV601962 A/G AGCATAGAGGACTTCCT AGCATAGAGGACTTCCT GTGCTGGGATTACAGGC GTTT  GTTC  AAGAG  (SEQ ID NO: 5114) (SEQ ID NO: 5115) (SEQ ID NO: 5116) hCV610861 C/T TGGTGCTTGTTAAAATT GTGGTGCTTGTTAAAAT CTAAATCAGGTTTATTT TGCTG  TTGCTA  GCCATGGAAGAGA  (SEQ ID NO: 5117) (SEQ ID NO: 5118) (SEQ ID NO: 5119) hCV621313 C/T TCCATGTGTCTGCTACC TCCATGTGTCTGCTACC CTCTTTCCCGGCATACC TC  TT  TGAAT  (SEQ ID NO: 5120) (SEQ ID NO: 5121) (SEQ ID NO: 5122) hCV7425232 C/T TCAAAATTATTTCTTGC GTCAAAATTATTTCTTG TCCTCCAGCCTCTCATT TACAGG  CTACAGA  C  (SEQ ID NO: 5123) (SEQ ID NO: 5124) (SEQ ID NO: 5125) hCV7435390 A/G GTGGCCAGGGAAACAT  GTGGCCAGGGAAACAC  CCATGGCGAAGCAAATA (SEQ ID NO: 5126) (SEQ ID NO: 5127) T  (SEQ ID NO: 5128) hCV7441704 A/G CCAACCGAGATCAGATT CAACCGAGATCAGATTG TGATGCTGATTGTGGAT GA  G  GATA  (SEQ ID NO: 5129) (SEQ ID NO: 5130) (SEQ ID NO: 5131) hCV7442005 A/G ACTTAACACTACTGAAC ACTTAACACTACTGAAC CACACACGCCCCTAAAC TGTACATTT  TGTACATTC  AATAGAT  (SEQ ID NO: 5132) (SEQ ID NO: 5133) (SEQ ID NO: 5134) hCV7442014 C/A AGCAAAACCTTACAAAT AGCAAAACCTTACAAAT TTACCACATTCATTGCA GTGAC  GTGAA TTTG  (SEQ ID NO: 5135) (SEQ ID NO: 5136) (SEQ ID NO: 5137) hCV7443062 T/C GGAGCAGGATGGTGAT  GGAGCAGGATGGTGAC  GGAAATATCTCGTTCTT (SEQ ID NO: 5138) (SEQ ID NO: 5139) GTTCTCT  (SEQ ID NO: 5140) hCV7451269 A/G CTTCCACTCAGCTTCTT TTCCACTCAGCTTCTTG GTAACGGGAGCCCCTAC GT  C  AC  (SEQ ID NO: 5141) (SEQ ID NO: 5142) (SEQ ID NO: 5143) hCV7475492 C/T CCAGACTTACCGATGTA CCAGACTTACCGATGTA GAGGGCCGCAGAGGT  GAC  GAT  (SEQ ID NO: 5146) (SEQ ID NO: 5144) (SEQ ID NO: 5145) hCV7480314 C/T GCATAGCCAAGGACTCC GCATAGCCAAGGACTCC AGGTGACAGGAGTCCCT AC  AT  ACAAC  (SEQ ID NO: 5147) (SEQ ID NO: 5148) (SEQ ID NO: 5149) hCV7490135 C/T GCAGTCCTGAACAAAGT CGCAGTCCTGAACAAAG CGTGCATGTTTTGAAAA AGATG  TAGATA  ATGTA  (SEQ ID NO: 5150) (SEQ ID NO: 5151) (SEQ ID NO: 5152) hCV7494810 C/G CCCGAGCGGACAGTG  CCCGAGCGGACAGTC  CAACTGCTGGCAGAATC (SEQ ID NO: 5153) (SEQ ID NO: 5154) TTC  (SEQ ID NO: 5155) hCV7499212 C/T GTGATGGTAGACACCTG TGTGATGGTAGACACCT GGCTGCACGGACTCTTC  GG  GGA  (SEQ ID NO: 5158) (SEQ ID NO: 5156) (SEQ ID NO: 5157) hCV7501549 C/T TCAGTTGTTGTGGGCTG  CTCAGTTGTTGTGGGCT GCCCACCTGCAAGGAAT (SEQ ID NO: 5159) A  AGAG  (SEQ ID NO: 5160) (SEQ ID NO: 5161) hCV7504854 A/G TCTGGTGCGTAGAATTC TGGTGCGTAGAATTCCC  ACAGCAGCAACGATCTC CT  (SEQ ID NO: 5163) A  (SEQ ID NO: 5162) (SEQ ID NO: 5164) hCV7514870 A/C GAGCAGCAGGTTTGAGG GCAGCAGGTTTGAGGG  ACACCACCTGAACGTCT T  (SEQ ID NO: 5166) CTT  (SEQ ID NO: 5165) (SEQ ID NO: 5167) hCV7514879 A/G GGCTGAACCCCGTCCT  GCTGAACCCCGTCCC  CTTTTTCCTGCATCCTG (SEQ ID NO: 5168) (SEQ ID NO: 5169) TCT  (SEQ ID NO: 5170) hCV7537517 C/G CAGACCCCATTTTACAA TCAGACCCCATTTTACA ACCTGGATTCTATTTTC TAAAGC  ATAAAGG  ATCCCATTACATAAGAG (SEQ ID NO: 5171) (SEQ ID NO: 5172) (SEQ ID NO: 5173) hCV7577801 C/T CTTTGCTGCTCTGCC  CCTTTGCTGCTCTGCT  GGTCTCTGGTATTAAGT (SEQ ID NO: 5174) (SEQ ID NO: 5175) GGAAACA  (SEQ ID NO: 5176) hCV7618856 C/T GGCTCCCAATGTTAGTG TGGCTCCCAATGTTAGT GGATTGGTTTGCATTTA C  GT  TTTTAGTA  (SEQ ID NO: 5177) (SEQ ID NO: 5178) (SEQ ID NO: 5179) hCV783138 A/G CATGCCACCCACTACCA  ATGCCACCCACTACCG  GAGCTTTTGCAGCCACT (SEQ ID NO: 5180) (SEQ ID NO: 5181) C  (SEQ ID NO: 5182) hCV783184 G/T TGCGAGTCAAATCTCAA TGCGAGTCAAATCTCAA CCTATTCCCGGCACTTC GAC  GAA  T  (SEQ ID NO: 5183) (SEQ ID NO: 5184) (SEQ ID NO: 5185) hCV7841642 A/G ACCAGCTCCAGGGTGTT  ACCAGCTCCAGGGTGTC  TGAAGTTTTGGAATGAG (SEQ ID NO: 5186) (SEQ ID NO: 5187) ACTGAT  (SEQ ID NO: 5188) hCV7900503 C/T CGTCTCCAGGAAAATCA CGTCTCCAGGAAAATCA TGAGTTATTGCTACTTC TAAC  TAAT  AGAATCAT  (SEQ ID NO: 5189) (SEQ ID NO: 5190) (SEQ ID NO: 5191) hCV7910239 A/G CACTTTGTAACCTAAGA ACTTTGTAACCTAAGAG GAGAACTCTAGTGAGTC GATGCT  ATGCC  TGTCCTTCAA  (SEQ ID NO: 5192) (SEQ ID NO: 5193) (SEQ ID NO: 5194) hCV795441 C/G TGTGGGCCAGGACG  CTGTGGGCCAGGACC  ACCCACCAGGACCTAAA (SEQ ID NO: 5195) (SEQ ID NO: 5196) AG  (SEQ ID NO: 5197) hCV795442 A/G CCATTCAATGCAATACG CATTCAATGCAATACGT CCTCTCCTTCCAGAACC TCA  CG  AGT  (SEQ ID NO: 5198) (SEQ ID NO: 5199) (SEQ ID NO: 5200) hCV8072964 A/T CCTGATATCCTTGTTCA CCTGATATCCTTGTTCA TGTTACGGCTGCTATAA TCAT  TCAA  TGTGT  (SEQ ID NO: 5201) (SEQ ID NO: 5202) (SEQ ID NO: 5203) hCV8157049 C/T AGAAGCTGTGTGTCTGG CAGAAGCTGTGTGTCTG TGGGTAGATGTGGAATC C  GT  AATAC  (SEQ ID NO: 5204) (SEQ ID NO: 5205) (SEQ ID NO: 5206) hCV818008 C/T GCGAGGTGAGCCCG  AGCGAGGTGAGCCCA  GGGATTATCCCAGGAAA (SEQ ID NO: 5207) (SEQ ID NO: 5208) GAC  (SEQ ID NO: 5209) hCV8369472 A/G CTTGACTGAAAAGTCTG TTGACTGAAAAGTCTGG GTTTCATGGAGGGCTCA GTCA  TCG  GAACT  (SEQ ID NO: 5210) (SEQ ID NO: 5211) (SEQ ID NO: 5212) hCV8379452 C/T TGATTGCTCTCCTTTGC GTGATTGCTCTCCTTTG CCACCTGTATCTGCCAT C  CT  TTCTCT  (SEQ ID NO: 5213) (SEQ ID NO: 5214) (SEQ ID NO: 5215) hCV8420416 C/T CATTATGAGGGTTACAA ACATTATGAGGGTTACA GGGAAACTCACTTCTGT GAATACTCC  AGAATACTCT  AGGTAA  (SEQ ID NO: 5216) (SEQ ID NO: 5217) (SEQ ID NO: 5218) hCV8687255 C/T CCTGCTTCAGAGGCTGA CCTGCTTCAGAGGCTGA CCTCTTCTGGCCTTTCC C  T  ATACAAT  (SEQ ID NO: 5219) (SEQ ID NO: 5220) (SEQ ID NO: 5221) hCV8696050 A/G GTGCCACGGTCAGGT  TGCCACGGTCAGGC  GTGCAACCACCACTTGT (SEQ ID NO: 5222) (SEQ ID NO: 5223) CTTTAGTT  (SEQ ID NO: 5224) hCV8696079 G/T CAACCTCAGTGGAAAGA TCAACCTCAGTGGAAAG GCCCATGTGCAAAGGTC TGC  ATGA  TCA  (SEQ ID NO: 5225) (SEQ ID NO: 5226) (SEQ ID NO: 5227) hCV8705506 C/G CCACTTCGGGTTCCTC  CCACTTCGGGTTCCTG  CCCTGGCTTCAACATGA  (SEQ ID NO: 5228) (SEQ ID NO: 5229) (SEQ ID NO: 5230) hCV8708473 A/G GCAACAGGACACCTGAA  GCAACAGGACACCTGAG  GAGTGACAGGAGGCTGC (SEQ ID NO: 5231) (SEQ ID NO: 5232) TTA  (SEQ ID NO: 5233) hCV8709053 A/G GCCCAGATACCCCAAAA  GCCCAGATACCCCAAAG  GCCCAGCCTGCGTAGA  (SEQ ID NO: 5234) (SEQ ID NO: 5235) (SEQ ID NO: 5236) hCV8718197 A/G CCTCTGAGGCCTGAGAA CCTCTGAGGCCTGAGAA GTCCTGATTCCTCATTT A  G  CTTTC  (SEQ ID NO: 5237) (SEQ ID NO: 5238) (SEQ ID NO: 5239) hCV8722613 C/T CCTGGGGCAGGTACAG  CCTGGGGCAGGTACAA  CCATCCACTGCTTGAAA (SEQ ID NO: 5240) (SEQ ID NO: 5241) AG  (SEQ ID NO: 5242) hCV8726337 A/G CACATTCACGGTCACCT CACATTCACGGTCACCT CATTGCCCGAGCTCAA  T  C  (SEQ ID NO: 5245) (SEQ ID NO: 5243) (SEQ ID NO: 5244) hCV8737990 C/T GTCCTTGCAAGTATCCG  GGTCCTTGCAAGTATCC GCACTACAGCTGAGTCC (SEQ ID NO: 5246) A  TTTTC  (SEQ ID NO: 5247) (SEQ ID NO: 5248) hCV8784787 A/C ACTTCTGGGGCTTAGGA ACTTCTGGGGCTTAGGA TTCACCGGGAACTCTTG A  C  T  (SEQ ID NO: 5249) (SEQ ID NO: 5250) (SEQ ID NO: 5251) hCV8785824 A/C ATTTACAGAAGCTGCAA ACAGAAGCTGCAAGAAC CATTTTCTGTTTCTGGA GAACT  G  TCTGGCAGTAG  (SEQ ID NO: 5252) (SEQ ID NO: 5253) (SEQ ID NO: 5254) hCV8785827 A/G AGCAAGAACCAGTGATA GCAAGAACCAGTGATAG CCTGTTGGCATGCTTGA GGTT  GTC  TGATG  (SEQ ID NO: 5255) (SEQ ID NO: 5256) (SEQ ID NO: 5257) hCV8804621 A/G AGGTTTCTTGGAGGAAG AGGTTTCTTGGAGGAAG GCACTGCACCCAGTGAG  AGAT  AGAC  (SEQ ID NO: 5260) (SEQ ID NO: 5258) (SEQ ID NO: 5259) hCV8804684 A/T TGTGTATATCCACGGCA TGTGTATATCCACGGCA TGCCCTCACCCAATATT TTAT  TTAA  C  (SEQ ID NO: 5261) (SEQ ID NO: 5262) (SEQ ID NO: 5263) hCV881283 C/G TCAGACACACAGGACAC TTCAGACACACAGGACA CCCTTCTGCTCCCAGAA ATG  CATC  C  (SEQ ID NO: 5264) (SEQ ID NO: 5265) (SEQ ID NO: 5266) hCV8823713 C/T CCGTTATAATCGAAGGG TCCGTTATAATCGAAGG GCTTCTCCACTTTCTCA ACAC  GACAT  CATCAGT  (SEQ ID NO: 5267) (SEQ ID NO: 5268) (SEQ ID NO: 5269) hCV8824241 G/A AACAGAAAACGAAGTGA TAACAGAAAACGAAGTG AGTTCAAGACGGGTCAT TCATC  ATCATT  ATTC  (SEQ ID NO: 5270) (SEQ ID NO: 5271) (SEQ ID NO: 5272) hCV8824244 C/T CCTGTTGACTGACTCAT TCCTGTTGACTGACTCA TTGGCCACATGTTCTAT AGGG  TAGGA  CTCTA  (SEQ ID NO: 5273) (SEQ ID NO: 5274) (SEQ ID NO: 5275) hCV8824248 A/G AAAGCATAGGATGGGGA AGCATAGGATGGGGACG  CCTGGGTGACAGAGTGA CA  (SEQ ID NO: 5277) GATTT  (SEQ ID NO: 5276) (SEQ ID NO: 5278) hCV8824394 G/T GTGAGTGTGATTTTGCT TGTGAGTGTGATTTTGC CCCAAACCCCCAGAGAA CAAC  TCAAA  TAAGT  (SEQ ID NO: 5279) (SEQ ID NO: 5280) (SEQ ID NO: 5281) hCV8824424 A/G CATGGTGACCCCACATT  CATGGTGACCCCACATC  CCCACACAGCATGCTTT (SEQ ID NO: 5282) (SEQ ID NO: 5283) CTGAAT  (SEQ ID NO: 5284) hCV8824425 A/C GTTGGGATAGGCTTGTT TTGGGATAGGCTTGTTT GCCTCCCTGTGAACAAA TTGT  TGG  CTAAAGT  (SEQ ID NO: 5285) (SEQ ID NO: 5286) (SEQ ID NO: 5287) hCV8824453 G/T TCCCTGAGGTGCTGAAG  TCCCTGAGGTGCTGAAT  GGCTGGTTCTGGCTTCT (SEQ ID NO: 5288) (SEQ ID NO: 5289) TTTATCTC  (SEQ ID NO: 5290) hCV8848630 G/T CATCTTCATCATCAAGG CATCTTCATCATCAAGG TGTTTTCCTCCCTCAGA GAG  GAT  TATCT  (SEQ ID NO: 5291) (SEQ ID NO: 5292) (SEQ ID NO: 5293) hCV8851047 T/C CCTCAAAGGAAAAGGCT CCTCAAAGGAAAAGGCT GCGGACCATGTGTCAAC T  C  T  (SEQ ID NO: 5294) (SEQ ID NO: 5295) (SEQ ID NO: 5296) hCV8851065 C/G CCCCGCAGAGAATTACC  CCCCGCAGAGAATTACG  ACGTCGCTGTCGAAGC  (SEQ ID NO: 5297) (SEQ ID NO: 5298) (SEQ ID NO: 5299) hCV8851085 A/G GCTCGTAGTTGTGTCTG GCTCGTAGTTGTGTCTG CGCTTCCTGGAGAGATA CAT  CAC  CAT  (SEQ ID NO: 5300) (SEQ ID NO: 5301) (SEQ ID NO: 5302) hCV8851095 C/T CTCCACTTGGCAGG  GCTCCACTTGGCAGA  CACCAACCTGATCCGTA (SEQ ID NO: 5303) (SEQ ID NO: 5304) ATG  (SEQ ID NO: 5305) hCV8881160 C/T TCCTAGAACATACAACA TCCTAGAACATACAACA GTGCCTAGCAGATGCCC GTTTTAGC  GTTTTAGT  AATAAATA  (SEQ ID NO: 5306) (SEQ ID NO: 5307) (SEQ ID NO: 5308) hCV8881161 A/G GAGAAAGTCCTCTATGA GAGAAAGTCCTCTATGA CCCCGTCTTTCTTATAT ACTGATAA  ACTGATAG  GAAGGGTAGAA  (SEQ ID NO: 5309) (SEQ ID NO: 5310) (SEQ ID NO: 5311) hCV8881164 C/T AGAACACAAAATTTCTG AAGAACACAAAATTTCT GATCCTCCCGGGCTCAA TGATACAC  GTGATACAT  GT  (SEQ ID NO: 5312) (SEQ ID NO: 5313) (SEQ ID NO: 5314) hCV8888179 C/T GCCCTCTGCACACCTTC  GCCCTCTGCACACCTTT  GGTAGGAGGATCTGCAG (SEQ ID NO: 5315) (SEQ ID NO: 5316) TTGT  (SEQ ID NO: 5317) hCV8892418 A/G GAGACCAGTCTGACTTA AGACCAGTCTGACTTAC GCCCGGCCTTCCTAGTA CACT  ACC  TT  (SEQ ID NO: 5318) (SEQ ID NO: 5319) (SEQ ID NO: 5320) hCV8895373 A/G AGGACTTCCGTGTCTT  AGGACTTCCGTGTCTC  ACAGATGCCAGCAATAC (SEQ ID NO: 5321) (SEQ ID NO: 5322) AGA  (SEQ ID NO: 5323) hCV8901525 G/A CAGCTCACGCAGCG  TCAGCTCACGCAGCA  CTTGTTGGAGTGTGTGA (SEQ ID NO: 5324) (SEQ ID NO: 5325) ATAAGA  (SEQ ID NO: 5326) hCV8921288 C/A CCGCAGAGGTGTGGG  CCGCAGAGGTGTGGT  CATTTTGCGGTGGAAAT (SEQ ID NO: 5327) (SEQ ID NO: 5328) G  (SEQ ID NO: 5329) hCV8936042 C/T ACGAGAATCTTCTCCTA ACGAGAATCTTCTCCTA GTGTGACCCACTCTTGA CACG  CACA  AAGACAT  (SEQ ID NO: 5330) (SEQ ID NO: 5331) (SEQ ID NO: 5332) hCV904973 C/T TCCTCCGCGATGCCGAT TCCTCCGCGATGCCGAT TCGCGGGCCCCGGCCTG GACCTGCAGAATC  GACCTGCAGAATT  GTACA  (SEQ ID NO: 5333) (SEQ ID NO: 5334) (SEQ ID NO: 5335) hCV904974 C/T GCCGGCACTCTCTTCC  GCCGGCACTCTCTTCT  CAGAGGGACAAGCAGAT (SEQ ID NO: 5336) (SEQ ID NO: 5337) GT  (SEQ ID NO: 5338) hCV9055799 C/G ACAGATCCATTTCATCT ACAGATCCATTTCATCT GGCTCTGGGAATTTCAC AGGTC  AGGTG  AT  (SEQ ID NO: 5339) (SEQ ID NO: 5340) (SEQ ID NO: 5341) hCV9077561 G/A AGAAGGTGGGATCCAAA AGAAGGTGGGATCCAAA AGAAACCATCATGCTGA C  T  GGT  (SEQ ID NO: 5342) (SEQ ID NO: 5343) (SEQ ID NO: 5344) hCV922535 A/G AAACCAAGACTCTGGCA AACCAAGACTCTGGCAA TTCCCAGCTGACCCAGT AAT  AC  TCT  (SEQ ID NO: 5345) (SEQ ID NO: 5346) (SEQ ID NO: 5347) hCV9326822 C/T CTCGGGACCAGTCCAG  CTCGGGACCAGTCCAA  CCGACAGCCGAGGAGA  (SEQ ID NO: 5348) (SEQ ID NO: 5349) (SEQ ID NO: 5350) hCV9494470 G/T AGGGATCCGCAAAGC  CAGGGATCCGCAAAGA  TCTTTCTGCCAGGTACA (SEQ ID NO: 5351) (SEQ ID NO: 5352) TCA  (SEQ ID NO: 5353) hCV9506149 A/T CTGCTGGCCGTCCT  TGCTGGCCGTCCA  ACTCACGCTTGCTTTGA (SEQ ID NO: 5354) (SEQ ID NO: 5355) CT  (SEQ ID NO: 5356) hCV9528413 G/C GTCGTCCTGCTGATTTC TCGTCCTGCTGATTTCG  GGAAGGCCGGGATACTC  C  (SEQ ID NO: 5358) (SEQ ID NO: 5359) (SEQ ID NO: 5357) hCV9549398 A/G TCCTGCACTGTATGATA CCTGCACTGTATGATAT CAAAAGTCAACAAATGT TATGTGA  ATGTGG  GTTTACATA  (SEQ ID NO: 5360) (SEQ ID NO: 5361) (SEQ ID NO: 5362) hCV9581635 C/G CTGGAGTAATAACAGGA CTGGAGTAATAACAGGA CACTGCAAGTCTGTCTC ATACTGTC  ATACTGTG  ACATAGGA  (SEQ ID NO: 5363) (SEQ ID NO: 5364) (SEQ ID NO: 5365) hCV9588862 C/T AGCTGAGGGAACAATAT AAGCTGAGGGAACAATA GCCACCTGGGAAAGGCT TAACG  TTAACA  AAAT  (SEQ ID NO: 5366) (SEQ ID NO: 5367) (SEQ ID NO: 5368) hCV9589513 C/G GTGATGGATGCCACTGT TGATGGATGCCACTGTG  CCTGAGTTTTTTGACAC C  (SEQ ID NO: 5370) ATCTCT  (SEQ ID NO: 5369) (SEQ ID NO: 5371) hCV9596963 A/G TGCCCCCAGCCAGAA  TGCCCCCAGCCAGAG  GGCCCTCCAGGATCTG  (SEQ ID NO: 5372) (SEQ ID NO: 5373) (SEQ ID NO: 5374) hCV9604851 A/G CCGCCTTGCAGATGAT  CCGCCTTGCAGATGAC  GGAGCTGGCCATTAGAA (SEQ ID NO: 5375) (SEQ ID NO: 5376) TC  (SEQ ID NO: 5377) hCV997884 A/G CGGTGTCAGCACCTTTG GGTGTCAGCACCTTTGG  CCCCCAAGCAACCACA  A  (SEQ ID NO: 5379) (SEQ ID NO: 5380) (SEQ ID NO: 5378) hDV68873046 A/T TGGGATGAATTCTTCAA TGGGATGAATTCTTCAA TGCTGGTGCCTGTACCT  TGATAAGAT  TGATAAGAA  (SEQ ID NO: 5383) (SEQ ID NO: 5381) (SEQ ID NO: 5382) hDV70661573 A/T CCTGTGGTCGCCATCAA  CCTGTGGTCGCCATCAT  TTCAGGCTGTTCAGACA (SEQ ID NO: 5384) (SEQ ID NO: 5385) GTAGTG  (SEQ ID NO: 5386) hDV70715669 A/T GATTTGATTGGAGTCCA GATTTGATTGGAGTCCA CTGCTCCCAGCTCCAGT GGAAA  GGAAT  TTATC  (SEQ ID NO: 5387) (SEQ ID NO: 5388) (SEQ ID NO: 5389) hDV70751699 A/T GGGCCATTTCTGCTGTA  GGGCCATTTCTGCTGTT  CCAGACCCCAACTCAGT (SEQ ID NO: 5390) (SEQ ID NO: 5391) AGTAGAT  (SEQ ID NO: 5392) hDV70751704 A/T CTCTTCTCGCCCCAGA  CTCTTCTCGCCCCAGT  AGAACACAGGCTTACAC (SEQ ID NO: 5393) (SEQ ID NO: 5394) GCTTTTC  (SEQ ID NO: 5395) hDV70751706 C/G GTGGCTTCGTCATGTAG GTGGCTTCGTCATGTAG CGTGTAAGCCTGTGTTC G  C  TTTCTGAA  (SEQ ID NO: 5396) (SEQ ID NO: 5397) (SEQ ID NO: 5398) hDV70797856 C/T AAAGGTGCAAAACATCC GAAAGGTGCAAAACATC CCCAGGCTAGTCTTGAA AATTC  CAATTT  CTTCT  (SEQ ID NO: 5399) (SEQ ID NO: 5400) (SEQ ID NO: 5401) hDV70938014 A/G ACTTTCGTCCTCTTCAT CTTTCGTCCTCTTCATA GGGGTTCACTCTTGGTA ACCTA  CCTG  CCTTCTT  (SEQ ID NO: 5402) (SEQ ID NO: 5403) (SEQ ID NO: 5404) hDV70973697 C/T GCCATGAGACATAACAT GCCATGAGACATAACAT CGGCTTAAGGCAGAACA GCTTC  GCTTT  TTTAGAGA  (SEQ ID NO: 5405) (SEQ ID NO: 5406) (SEQ ID NO: 5407) hDV70977122 A/G GGACAGTGGTGCTAGTA GGACAGTGGTGCTAGTA ACCCTGACCACTCTGGA GTT  GTC  ACATAC  (SEQ ID NO: 5408) (SEQ ID NO: 5409) (SEQ ID NO: 5410) hDV76976592 A/G CTTCCAGAAAGCTCTGG TCCAGAAAGCTCTGGGG  CAGGTCAACAGAGCCTA GA  (SEQ ID NO: 5412) CGAATAAT  (SEQ ID NO: 5411) (SEQ ID NO: 5413)

TABLE 6 Interrogated SNP Interrogated (hCV #) SNP (rs #) LD SNP (hCV #) LD SNP (rs #) Power Threshold r² r² hCV10048483 rs2145270 hCV10048484 rs1000972 0.51 0.9 0.9242 hCV10048483 rs2145270 hCV10048501 rs979012 0.51 0.9 0.9242 hCV10048483 rs2145270 hCV2513354 rs6054427 0.51 0.9 1 hCV1026586 rs673548 hCV11168489 rs2678379 0.51 0.9 1 hCV1026586 rs673548 hCV11168524 rs6544366 0.51 0.9 0.9441 hCV1026586 rs673548 hCV11168530 rs6728178 0.51 0.9 0.9441 hCV1026586 rs673548 hCV260164 rs6754295 0.51 0.9 0.9441 hCV1026586 rs673548 hCV30847428 rs11902417 0.51 0.9 0.9441 hCV1026586 rs673548 hCV3216558 rs676210 0.51 0.9 1 hCV1026586 rs673548 hCV7615376 rs1042034 0.51 0.9 0.9709 hCV11170747 rs2066853 hCV15956280 rs2237297 0.51 0.9 1 hCV11170747 rs2066853 hCV16163703 rs2074113 0.51 0.9 1 hCV11170747 rs2066853 hCV29793055 rs10274243 0.51 0.9 1 hCV11231076 rs4857855 hCV487869 rs4431128 0.51 0.9 1 hCV11398434 rs1812457 hCV11398437 rs1817367 0.51 0.515519235 1 hCV11398434 rs1812457 hCV11675962 rs10746481 0.51 0.515519235 0.9381 hCV11398434 rs1812457 hCV1188731 rs4908514 0.51 0.515519235 0.8094 hCV11398434 rs1812457 hCV1188735 rs10864366 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV15882429 rs2289732 0.51 0.515519235 0.5975 hCV11398434 rs1812457 hCV15932991 rs2781067 0.51 0.515519235 0.5861 hCV11398434 rs1812457 hCV27157507 rs6664000 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV27157524 rs6577531 0.51 0.515519235 0.7539 hCV11398434 rs1812457 hCV2741759 rs11121179 0.51 0.515519235 0.5747 hCV11398434 rs1812457 hCV27884601 rs4908776 0.51 0.515519235 0.8089 hCV11398434 rs1812457 hCV27958354 rs4908762 0.51 0.515519235 0.8759 hCV11398434 rs1812457 hCV28023091 rs4908773 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV29368919 rs4908513 0.51 0.515519235 0.8094 hCV11398434 rs1812457 hCV2943451 rs902355 0.51 0.515519235 0.6736 hCV11398434 rs1812457 hCV2943853 rs301793 0.51 0.515519235 0.5975 hCV11398434 rs1812457 hCV2966436 rs11121174 0.51 0.515519235 0.5975 hCV11398434 rs1812457 hCV2966437 rs11580417 0.51 0.515519235 0.5975 hCV11398434 rs1812457 hCV2966441 rs6684863 0.51 0.515519235 0.5975 hCV11398434 rs1812457 hCV2966444 rs11121171 0.51 0.515519235 0.6417 hCV11398434 rs1812457 hCV29819064 rs6698079 0.51 0.515519235 1 hCV11398434 rs1812457 hCV2987250 rs301810 0.51 0.515519235 0.7861 hCV11398434 rs1812457 hCV29873524 rs7533113 0.51 0.515519235 0.8094 hCV11398434 rs1812457 hCV29873526 rs6697997 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV29945430 rs7517436 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV30035535 rs7518204 0.51 0.515519235 0.8087 hCV11398434 rs1812457 hCV30125699 rs4581300 0.51 0.515519235 0.8759 hCV11398434 rs1812457 hCV30143725 rs6690050 0.51 0.515519235 0.9381 hCV11398434 rs1812457 hCV30467730 rs6702457 0.51 0.515519235 0.9381 hCV11398434 rs1812457 hCV3086930 rs6658881 0.51 0.515519235 0.9345 hCV11398434 rs1812457 hCV3086932 rs7533442 0.51 0.515519235 0.9345 hCV11398434 rs1812457 hCV3086950 rs4908771 0.51 0.515519235 0.9381 hCV11398434 rs1812457 hCV3086961 rs6703577 0.51 0.515519235 1 hCV11398434 rs1812457 hCV3086971 rs6679948 0.51 0.515519235 1 hCV11398434 rs1812457 hCV3086972 rs6688329 0.51 0.515519235 1 hCV11398434 rs1812457 hCV3086998 rs7530863 0.51 0.515519235 0.8759 hCV11398434 rs1812457 hCV3087000 rs1463055 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV3087003 rs6577500 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV3087015 rs11121198 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV3087016 rs2297867 0.51 0.515519235 0.8759 hCV11398434 rs1812457 hCV32055284 rs12079653 0.51 0.515519235 0.6858 hCV11398434 rs1812457 hCV32055470 rs6577506 0.51 0.515519235 1 hCV11398434 rs1812457 hCV32055474 rs10864359 0.51 0.515519235 1 hCV11398434 rs1812457 hCV32055477 rs10779705 0.51 0.515519235 1 hCV11398434 rs1812457 hCV32055527 rs10864364 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV32055548 rs11121197 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV32055579 rs6577522 0.51 0.515519235 0.8092 hCV11398434 rs1812457 hCV32055595 rs6577524 0.51 0.515519235 0.8094 hCV11398434 rs1812457 hCV32055596 rs6577525 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV32055625 rs6678590 0.51 0.515519235 0.7684 hCV11398434 rs1812457 hCV32055637 rs6577532 0.51 0.515519235 0.7394 hCV11398434 rs1812457 hCV32055662 rs6677249 0.51 0.515519235 0.5758 hCV11398434 rs1812457 hCV32055677 rs10864355 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV529178 rs301811 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV529182 rs301800 0.51 0.515519235 0.6217 hCV11398434 rs1812457 hCV597227 rs301809 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV597229 rs301785 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV877241 rs301788 0.51 0.515519235 0.5747 hCV11398434 rs1812457 hCV8823713 rs1472228 0.51 0.515519235 0.7979 hCV11398434 rs1812457 hCV8824288 rs910582 0.51 0.515519235 0.8824 hCV11398434 rs1812457 hCV8824394 rs1443929 0.51 0.515519235 0.5747 hCV11398434 rs1812457 hCV8824424 rs1058790 0.51 0.515519235 0.6417 hCV11398434 rs1812457 hCV8824425 rs1058791 0.51 0.515519235 0.62 hCV11398434 rs1812457 hCV8881145 rs1038008 0.51 0.515519235 1 hCV11398434 rs1812457 hCV8881146 rs1463054 0.51 0.515519235 1 hCV11398434 rs1812457 hCV8881157 rs1535158 0.51 0.515519235 1 hCV11398434 rs1812457 hCV8881161 rs926951 0.51 0.515519235 0.8759 hCV11398437 rs1817367 hCV11398434 rs1812457 0.51 0.883097369 1 hCV11398437 rs1817367 hCV11675962 rs10746481 0.51 0.883097369 0.9276 hCV11398437 rs1817367 hCV27958354 rs4908762 0.51 0.883097369 0.8987 hCV11398437 rs1817367 hCV29819064 rs6698079 0.51 0.883097369 1 hCV11398437 rs1817367 hCV30125699 rs4581300 0.51 0.883097369 0.8936 hCV11398437 rs1817367 hCV30143725 rs6690050 0.51 0.883097369 0.9276 hCV11398437 rs1817367 hCV30467730 rs6702457 0.51 0.883097369 0.9276 hCV11398437 rs1817367 hCV3086950 rs4908771 0.51 0.883097369 0.9276 hCV11398437 rs1817367 hCV3086961 rs6703577 0.51 0.883097369 0.9642 hCV11398437 rs1817367 hCV3086971 rs6679948 0.51 0.883097369 1 hCV11398437 rs1817367 hCV3086972 rs6688329 0.51 0.883097369 1 hCV11398437 rs1817367 hCV3086998 rs7530863 0.51 0.883097369 0.8987 hCV11398437 rs1817367 hCV32055470 rs6577506 0.51 0.883097369 0.9642 hCV11398437 rs1817367 hCV32055474 rs10864359 0.51 0.883097369 0.8987 hCV11398437 rs1817367 hCV32055477 rs10779705 0.51 0.883097369 1 hCV11398437 rs1817367 hCV8881145 rs1038008 0.51 0.883097369 1 hCV11398437 rs1817367 hCV8881146 rs1463054 0.51 0.883097369 1 hCV11398437 rs1817367 hCV8881157 rs1535158 0.51 0.883097369 1 hCV11398437 rs1817367 hCV8881161 rs926951 0.51 0.883097369 0.8987 hCV11438723 rs1877273 hCV15830836 rs2859641 0.51 0.9 1 hCV11438723 rs1877273 hCV15868592 rs2941949 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV15912032 rs2667617 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV15912048 rs2667611 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV15912085 rs2667632 0.51 0.9 1 hCV11438723 rs1877273 hCV15912105 rs2667623 0.51 0.9 1 hCV11438723 rs1877273 hCV1592156 rs2738745 0.51 0.9 0.9549 hCV11438723 rs1877273 hCV1592157 rs2667614 0.51 0.9 1 hCV11438723 rs1877273 hCV1592158 rs3106331 0.51 0.9 1 hCV11438723 rs1877273 hCV16290607 rs2738494 0.51 0.9 1 hCV11438723 rs1877273 hCV16290609 rs2257074 0.51 0.9 1 hCV11438723 rs1877273 hCV16291171 rs2738743 0.51 0.9 0.9082 hCV11438723 rs1877273 hCV27271636 rs2941952 0.51 0.9 1 hCV11438723 rs1877273 hCV8897017 rs2859644 0.51 0.9 1 hCV11438723 rs1877273 hCV8897018 rs1105313 0.51 0.9 1 hCV11446935 rs2409722 hCV231938 rs7813802 0.51 0.9 0.9623 hCV11446935 rs2409722 hCV30011529 rs7819412 0.51 0.9 1 hCV11568668 rs1317538 hCV502935 rs12526735 0.51 0.9 1 hCV11568668 rs1317538 hCV502936 rs1317537 0.51 0.9 0.9429 hCV11592758 rs6265 hCV12035465 rs2049045 0.51 0.9 1 hCV11592758 rs6265 hCV30726493 rs11030084 0.51 0.9 1 hCV11678789 rs7219148 hCV2536560 rs11078773 0.51 0.9 1 hCV11697322 rs1926447 hCV11697321 rs1926446 0.51 0.9 1 hCV11697322 rs1926447 hCV16228638 rs2404727 0.51 0.9 0.9127 hCV11761245 rs7043149 hCV11759640 rs7850573 0.51 0.493197647 0.6145 hCV11761245 rs7043149 hCV11759644 rs6560584 0.51 0.493197647 0.6145 hCV11761245 rs7043149 hCV11759645 rs7034303 0.51 0.493197647 0.6145 hCV11761245 rs7043149 hCV11759647 rs7048937 0.51 0.493197647 0.6145 hCV11761245 rs7043149 hCV11760387 rs2309422 0.51 0.493197647 0.6665 hCV11761245 rs7043149 hCV11760421 rs12056979 0.51 0.493197647 0.6798 hCV11761245 rs7043149 hCV11761216 rs7874888 0.51 0.493197647 0.6376 hCV11761245 rs7043149 hCV11761223 rs2309426 0.51 0.493197647 0.6358 hCV11761245 rs7043149 hCV11761237 rs4329331 0.51 0.493197647 0.6712 hCV11761245 rs7043149 hCV11761239 rs4338173 0.51 0.493197647 0.6684 hCV11761245 rs7043149 hCV1844076 rs1339546 0.51 0.493197647 0.6528 hCV11761245 rs7043149 hCV20896 rs2309424 0.51 0.493197647 0.6528 hCV11761245 rs7043149 hCV25805877 rs3750549 0.51 0.493197647 0.6518 hCV11761245 rs7043149 hCV26566188 rs4375066 0.51 0.493197647 0.6742 hCV11761245 rs7043149 hCV26566190 rs3927676 0.51 0.493197647 0.6742 hCV11761245 rs7043149 hCV26566432 rs4076288 0.51 0.493197647 0.8065 hCV11761245 rs7043149 hCV26566437 rs4421408 0.51 0.493197647 0.6798 hCV11761245 rs7043149 hCV26566445 rs4339703 0.51 0.493197647 0.8124 hCV11761245 rs7043149 hCV27970553 rs5006364 0.51 0.493197647 0.8124 hCV11761245 rs7043149 hCV27996874 rs4745701 0.51 0.493197647 0.944 hCV11761245 rs7043149 hCV29169289 rs6560585 0.51 0.493197647 0.6145 hCV11761245 rs7043149 hCV29577088 rs9314865 0.51 0.493197647 0.6528 hCV11761245 rs7043149 hCV29830130 rs10217168 0.51 0.493197647 0.6528 hCV11761245 rs7043149 hCV30172680 rs10122932 0.51 0.493197647 0.6237 hCV11761245 rs7043149 hCV30532761 rs10125494 0.51 0.493197647 0.6798 hCV11761245 rs7043149 hCV31363642 rs7862404 0.51 0.493197647 0.6667 hCV11761245 rs7043149 hCV31363652 rs10869961 0.51 0.493197647 0.6798 hCV11761245 rs7043149 hCV31363664 rs10869975 0.51 0.493197647 0.6433 hCV11761245 rs7043149 hCV31363697 rs7041781 0.51 0.493197647 0.639 hCV11761245 rs7043149 hCV31364135 rs10781440 0.51 0.493197647 0.6334 hCV11761245 rs7043149 hCV31364138 rs7865373 0.51 0.493197647 0.6334 hCV11761245 rs7043149 hCV31364140 rs7467352 0.51 0.493197647 0.6721 hCV11761245 rs7043149 hCV31364141 rs11145460 0.51 0.493197647 0.699 hCV11761245 rs7043149 hCV446682 rs2309427 0.51 0.493197647 0.6376 hCV11761245 rs7043149 hCV450641 rs10781456 0.51 0.493197647 0.6334 hCV11761245 rs7043149 hCV453560 rs10869992 0.51 0.493197647 0.6687 hCV11761245 rs7043149 hCV453561 rs10869993 0.51 0.493197647 0.6694 hCV11761245 rs7043149 hCV453562 rs10869994 0.51 0.493197647 0.6712 hCV11761245 rs7043149 hCV453563 rs10869997 0.51 0.493197647 0.6848 hCV11761245 rs7043149 hCV456556 rs4076287 0.51 0.493197647 0.6762 hCV11761245 rs7043149 hCV463630 rs2486451 0.51 0.493197647 1 hCV11761245 rs7043149 hCV500456 rs10869976 0.51 0.493197647 0.7161 hCV11761245 rs7043149 hCV7441996 rs867346 0.51 0.493197647 0.6897 hCV11761245 rs7043149 hCV7442003 rs884428 0.51 0.493197647 0.6742 hCV11761245 rs7043149 hCV7442004 rs884429 0.51 0.493197647 0.6742 hCV11761245 rs7043149 hCV7442005 rs1538584 0.51 0.493197647 1 hCV11761245 rs7043149 hCV7482544 rs1416738 0.51 0.493197647 0.6334 hCV11761245 rs7043149 hDV70840481 rs17062237 0.51 0.493197647 0.6712 hCV11761245 rs7043149 hDV71162544 rs1416739 0.51 0.493197647 0.6838 hCV11761245 rs7043149 hDV81101901 rs4745650 0.51 0.493197647 0.6798 hCV11764545 rs4961 hCV15955503 rs2237004 0.51 0.9 0.9709 hCV11764545 rs4961 hCV15962694 rs2285084 0.51 0.9 0.9715 hCV11764545 rs4961 hCV16175508 rs2239728 0.51 0.9 0.9715 hCV11764545 rs4961 hCV7565684 rs4964 0.51 0.9 0.9151 hCV11764545 rs4961 hDV70681024 rs16843523 0.51 0.9 0.9182 hCV11846435 rs6929299 hCV103951 rs6455688 0.51 0.312678096 0.8095 hCV11846435 rs6929299 hCV103951 rs6455688 0.51 0.350657214 0.8095 hCV11846435 rs6929299 hCV103952 rs6923877 0.51 0.312678096 0.8095 hCV11846435 rs6929299 hCV103952 rs6923877 0.51 0.350657214 0.8095 hCV11846435 rs6929299 hCV11226249 rs6415085 0.51 0.312678096 1 hCV11846435 rs6929299 hCV11226249 rs6415085 0.51 0.350657214 1 hCV11846435 rs6929299 hCV11284288 rs9457946 0.51 0.312678096 0.748 hCV11846435 rs6929299 hCV11284288 rs9457946 0.51 0.350657214 0.748 hCV11846435 rs6929299 hCV11285578 rs6926458 0.51 0.312678096 0.5122 hCV11846435 rs6929299 hCV11285578 rs6926458 0.51 0.350657214 0.5122 hCV11846435 rs6929299 hCV11326233 rs1950562 0.51 0.312678096 0.5177 hCV11846435 rs6929299 hCV11326233 rs1950562 0.51 0.350657214 0.5177 hCV11846435 rs6929299 hCV1550866 rs6932014 0.51 0.312678096 1 hCV11846435 rs6929299 hCV1550866 rs6932014 0.51 0.350657214 1 hCV11846435 rs6929299 hCV1550871 rs9355295 0.51 0.312678096 0.7601 hCV11846435 rs6929299 hCV1550871 rs9355295 0.51 0.350657214 0.7601 hCV11846435 rs6929299 hCV16074739 rs2144723 0.51 0.312678096 0.3144 hCV11846435 rs6929299 hCV207123 rs7771801 0.51 0.312678096 0.7556 hCV11846435 rs6929299 hCV207123 rs7771801 0.51 0.350657214 0.7556 hCV11846435 rs6929299 hCV207127 rs7453899 0.51 0.312678096 0.8123 hCV11846435 rs6929299 hCV207127 rs7453899 0.51 0.350657214 0.8123 hCV11846435 rs6929299 hCV207128 rs6455689 0.51 0.312678096 0.7581 hCV11846435 rs6929299 hCV207128 rs6455689 0.51 0.350657214 0.7581 hCV11846435 rs6929299 hCV243055 rs10945682 0.51 0.312678096 1 hCV11846435 rs6929299 hCV243055 rs10945682 0.51 0.350657214 1 hCV11846435 rs6929299 hCV249895 rs7771129 0.51 0.312678096 1 hCV11846435 rs6929299 hCV249895 rs7771129 0.51 0.350657214 1 hCV11846435 rs6929299 hCV249897 rs6913833 0.51 0.312678096 0.9266 hCV11846435 rs6929299 hCV249897 rs6913833 0.51 0.350657214 0.9266 hCV11846435 rs6929299 hCV249898 rs9456552 0.51 0.312678096 1 hCV11846435 rs6929299 hCV249898 rs9456552 0.51 0.350657214 1 hCV11846435 rs6929299 hCV25927459 rs3798221 0.51 0.312678096 0.3835 hCV11846435 rs6929299 hCV25927459 rs3798221 0.51 0.350657214 0.3835 hCV11846435 rs6929299 hCV25929408 rs7765781 0.51 0.312678096 0.7601 hCV11846435 rs6929299 hCV25929408 rs7765781 0.51 0.350657214 0.7601 hCV11846435 rs6929299 hCV25929478 rs7765803 0.51 0.312678096 0.8123 hCV11846435 rs6929299 hCV25929478 rs7765803 0.51 0.350657214 0.8123 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0.312678096 0.8881 hCV11846435 rs6929299 hCV29817515 rs9355817 0.51 0.350657214 0.8881 hCV11846435 rs6929299 hCV29934611 rs9295130 0.51 0.312678096 0.9801 hCV11846435 rs6929299 hCV29934611 rs9295130 0.51 0.350657214 0.9801 hCV11846435 rs6929299 hCV29998162 rs9457943 0.51 0.312678096 0.7601 hCV11846435 rs6929299 hCV29998162 rs9457943 0.51 0.350657214 0.7601 hCV11846435 rs6929299 hCV30182157 rs7767705 0.51 0.312678096 0.3354 hCV11846435 rs6929299 hCV30385112 rs9365201 0.51 0.312678096 0.3179 hCV11846435 rs6929299 hCV305046 rs6902102 0.51 0.312678096 1 hCV11846435 rs6929299 hCV305046 rs6902102 0.51 0.350657214 1 hCV11846435 rs6929299 hCV30574599 rs7770628 0.51 0.312678096 0.5719 hCV11846435 rs6929299 hCV30574599 rs7770628 0.51 0.350657214 0.5719 hCV11846435 rs6929299 hCV31882494 rs12175867 0.51 0.312678096 0.5349 hCV11846435 rs6929299 hCV31882494 rs12175867 0.51 0.350657214 0.5349 hCV11846435 rs6929299 hCV3201490 rs1321195 0.51 0.312678096 0.3278 hCV11846435 rs6929299 hCV3201494 rs1367209 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hCV11864162 rs1167998 hCV11865171 rs11208004 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV11865185 rs10789117 0.51 0.9 0.9791 hCV11864162 rs1167998 hCV11865196 rs7555577 0.51 0.9 0.919 hCV11864162 rs1167998 hCV11865201 rs10159255 0.51 0.9 0.9376 hCV11864162 rs1167998 hCV12103105 rs1184865 0.51 0.9 1 hCV11864162 rs1167998 hCV12103127 rs1979722 0.51 0.9 0.9373 hCV11864162 rs1167998 hCV12103499 rs2029763 0.51 0.9 0.9558 hCV11864162 rs1167998 hCV12103502 rs1168023 0.51 0.9 1 hCV11864162 rs1167998 hCV1236535 rs1168042 0.51 0.9 1 hCV11864162 rs1167998 hCV149783 rs1168045 0.51 0.9 0.9791 hCV11864162 rs1167998 hCV16214290 rs2366638 0.51 0.9 1 hCV11864162 rs1167998 hCV1778957 rs3913007 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV1778958 rs634341 0.51 0.9 1 hCV11864162 rs1167998 hCV1778961 rs630144 0.51 0.9 0.9164 hCV11864162 rs1167998 hCV1778963 rs10158897 0.51 0.9 0.9376 hCV11864162 rs1167998 hCV1778964 rs659656 0.51 0.9 0.959 hCV11864162 rs1167998 hCV1778965 rs637723 0.51 0.9 0.9583 hCV11864162 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hCV11864162 rs1167998 hCV31145264 rs10789119 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV31145266 rs10789118 0.51 0.9 0.959 hCV11864162 rs1167998 hCV31145267 rs11485618 0.51 0.9 0.9576 hCV11864162 rs1167998 hCV31145269 rs6587980 0.51 0.9 0.9791 hCV11864162 rs1167998 hCV31145277 rs10889350 0.51 0.9 1 hCV11864162 rs1167998 hCV31145279 rs10889349 0.51 0.9 1 hCV11864162 rs1167998 hCV31145282 rs11207997 0.51 0.9 0.9169 hCV11864162 rs1167998 hCV31145290 rs12042319 0.51 0.9 0.959 hCV11864162 rs1167998 hCV31145291 rs11207995 0.51 0.9 0.9373 hCV11864162 rs1167998 hCV31145298 rs11207992 0.51 0.9 0.959 hCV11864162 rs1167998 hCV31145302 rs12116574 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV31145332 rs11207981 0.51 0.9 1 hCV11864162 rs1167998 hCV3122390 rs1748200 0.51 0.9 1 hCV11864162 rs1167998 hCV316299 rs1168026 0.51 0.9 1 hCV11864162 rs1167998 hCV316303 rs1168031 0.51 0.9 1 hCV11864162 rs1167998 hCV32220452 rs12090886 0.51 0.9 1 hCV11864162 rs1167998 hCV32220453 rs10889337 0.51 0.9 1 hCV11864162 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hCV11864162 rs1167998 hCV9508668 rs1781195 0.51 0.9 0.9791 hCV11864162 rs1167998 hCV9581062 rs998403 0.51 0.9 0.958 hCV11864162 rs1167998 hCV9581551 rs1168040 0.51 0.9 0.9364 hCV11864162 rs1167998 hCV9581570 rs1168036 0.51 0.9 1 hCV11864162 rs1167998 hCV9581571 rs1002687 0.51 0.9 1 hCV11864162 rs1167998 hCV9581580 rs1168032 0.51 0.9 1 hCV11864162 rs1167998 hCV9581581 rs1168030 0.51 0.9 1 hCV11864162 rs1167998 hCV9581590 rs1168018 0.51 0.9 0.979 hCV11864162 rs1167998 hCV9581606 rs1168022 0.51 0.9 1 hCV11864162 rs1167998 hCV9581615 rs1748201 0.51 0.9 0.979 hCV11864162 rs1167998 hCV9581635 rs1748195 0.51 0.9 0.9791 hCV11864162 rs1167998 hCV9581636 rs3850634 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV9581680 rs1748197 0.51 0.9 1 hCV11864162 rs1167998 hCV9581691 rs1570694 0.51 0.9 0.9585 hCV11864162 rs1167998 hCV9583244 rs783291 0.51 0.9 1 hCV11864162 rs1167998 hCV9588770 rs1007205 0.51 0.9 1 hCV11864162 rs1167998 hCV9588793 rs1168009 0.51 0.9 0.9789 hCV11864162 rs1167998 hCV9588794 rs1168010 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rs6577513 0.51 0.490752814 0.6112 hCV1188747 rs4908511 hCV29368927 rs6577499 0.51 0.490752814 0.5859 hCV1188747 rs4908511 hCV29368929 rs6577502 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV29674579 rs7542312 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV29855298 rs6690928 0.51 0.490752814 0.9259 hCV1188747 rs4908511 hCV29981708 rs7554486 0.51 0.490752814 0.8421 hCV1188747 rs4908511 hCV30233466 rs7513880 0.51 0.490752814 0.8871 hCV1188747 rs4908511 hCV30287627 rs6675443 0.51 0.490752814 0.6014 hCV1188747 rs4908511 hCV30341660 rs6681362 0.51 0.490752814 0.6064 hCV1188747 rs4908511 hCV30413939 rs6701331 0.51 0.490752814 0.589 hCV1188747 rs4908511 hCV30413946 rs7537982 0.51 0.490752814 0.6203 hCV1188747 rs4908511 hCV3086941 rs7556169 0.51 0.490752814 0.6368 hCV1188747 rs4908511 hCV3086945 rs6695867 0.51 0.490752814 0.6695 hCV1188747 rs4908511 hCV3086948 rs10864361 0.51 0.490752814 0.6532 hCV1188747 rs4908511 hCV3086949 rs11121212 0.51 0.490752814 0.7081 hCV1188747 rs4908511 hCV3086952 rs6577514 0.51 0.490752814 0.6232 hCV1188747 rs4908511 hCV3086954 rs1463053 0.51 0.490752814 0.6047 hCV1188747 rs4908511 hCV3086956 rs1463052 0.51 0.490752814 0.589 hCV1188747 rs4908511 hCV3086959 rs7520025 0.51 0.490752814 0.6689 hCV1188747 rs4908511 hCV3086965 rs1381928 0.51 0.490752814 0.6427 hCV1188747 rs4908511 hCV3086974 rs1318218 0.51 0.490752814 0.6354 hCV1188747 rs4908511 hCV3086976 rs11121204 0.51 0.490752814 0.5977 hCV1188747 rs4908511 hCV3086978 rs7526171 0.51 0.490752814 0.6419 hCV1188747 rs4908511 hCV3086981 rs6670508 0.51 0.490752814 0.6427 hCV1188747 rs4908511 hCV3086985 rs6663123 0.51 0.490752814 0.6427 hCV1188747 rs4908511 hCV3086990 rs11121202 0.51 0.490752814 0.6427 hCV1188747 rs4908511 hCV3087002 rs1473420 0.51 0.490752814 0.5859 hCV1188747 rs4908511 hCV3087004 rs2016084 0.51 0.490752814 0.4917 hCV1188747 rs4908511 hCV3087005 rs6702060 0.51 0.490752814 0.5703 hCV1188747 rs4908511 hCV3087012 rs1463051 0.51 0.490752814 0.5859 hCV1188747 rs4908511 hCV32055336 rs12080583 0.51 0.490752814 0.5794 hCV1188747 rs4908511 hCV32055351 rs12046643 0.51 0.490752814 0.5654 hCV1188747 rs4908511 hCV32055354 rs4908761 0.51 0.490752814 0.5823 hCV1188747 rs4908511 hCV32055465 rs6668508 0.51 0.490752814 0.5859 hCV1188747 rs4908511 hCV32055479 rs11121210 0.51 0.490752814 0.6118 hCV1188747 rs4908511 hCV32055489 rs10864360 0.51 0.490752814 0.7081 hCV1188747 rs4908511 hCV32055490 rs6669503 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV32055496 rs11121215 0.51 0.490752814 0.6433 hCV1188747 rs4908511 hCV32055498 rs4908507 0.51 0.490752814 0.6692 hCV1188747 rs4908511 hCV32055554 rs12024032 0.51 0.490752814 0.9804 hCV1188747 rs4908511 hCV32055587 rs10864367 0.51 0.490752814 0.8871 hCV1188747 rs4908511 hCV32055588 rs12131864 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV32055630 rs4908518 0.51 0.490752814 0.8148 hCV1188747 rs4908511 hCV32056071 rs11121201 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV32392515 rs4908505 0.51 0.490752814 0.6532 hCV1188747 rs4908511 hCV597221 rs301814 0.51 0.490752814 0.574 hCV1188747 rs4908511 hCV8379452 rs4908781 0.51 0.490752814 0.7134 hCV1188747 rs4908511 hCV8881153 rs1061039 0.51 0.490752814 0.6427 hCV1188747 rs4908511 hDV75072264 rs12403640 0.51 0.490752814 0.9612 hCV1188747 rs4908511 hDV77058075 rs4908506 0.51 0.490752814 0.6368 hCV11955747 rs9901673 hCV247220 rs6608 0.51 0.9 0.9705 hCV11955747 rs9901673 hCV26603808 rs4542712 0.51 0.9 1 hCV11955747 rs9901673 hCV31413193 rs10852891 0.51 0.9 1 hCV11972326 rs5988 hCV11322865 rs3024455 0.51 0.9 1 hCV11972326 rs5988 hCV11322900 rs3024458 0.51 0.9 1 hCV11972326 rs5988 hCV11322912 rs9504688 0.51 0.9 0.9502 hCV11972326 rs5988 hCV11972327 rs5980 0.51 0.9 1 hCV11972326 rs5988 hCV15983503 rs3024456 0.51 0.9 1 hCV11972326 rs5988 hCV15983508 rs2274394 0.51 0.9 1 hCV11972326 rs5988 hCV1860557 rs4960166 0.51 0.9 0.9527 hCV11972326 rs5988 hCV1860558 rs2170618 0.51 0.9 0.9505 hCV11972326 rs5988 hCV1860559 rs13211082 0.51 0.9 0.9505 hCV11972326 rs5988 hCV1860560 rs13203617 0.51 0.9 0.9527 hCV11972326 rs5988 hCV1860561 rs9504686 0.51 0.9 0.9527 hCV11972326 rs5988 hCV1860567 rs3799564 0.51 0.9 0.9505 hCV11972326 rs5988 hCV1860574 rs13203312 0.51 0.9 1 hCV11972326 rs5988 hCV1860575 rs6937073 0.51 0.9 1 hCV11972326 rs5988 hCV1860576 rs6914953 0.51 0.9 1 hCV11972326 rs5988 hCV1860577 rs6913691 0.51 0.9 1 hCV11972326 rs5988 hCV1860580 rs6899562 0.51 0.9 1 hCV11972326 rs5988 hCV1860582 rs35010441 0.51 0.9 1 hCV11972326 rs5988 hCV1860590 rs4960169 0.51 0.9 1 hCV11972326 rs5988 hCV1860592 rs6912528 0.51 0.9 1 hCV11972326 rs5988 hCV27953512 rs4282440 0.51 0.9 1 hCV11972326 rs5988 hCV28018442 rs4282441 0.51 0.9 1 hCV11972326 rs5988 hCV29167515 rs6936882 0.51 0.9 1 hCV11972326 rs5988 hCV29167516 rs6913645 0.51 0.9 1 hCV11972326 rs5988 hCV29992410 rs9502419 0.51 0.9 0.9512 hCV11972326 rs5988 hCV30190386 rs9504681 0.51 0.9 0.9021 hCV11972326 rs5988 hCV30460540 rs9504684 0.51 0.9 0.9496 hCV11972326 rs5988 hCV31360336 rs13194966 0.51 0.9 1 hCV11972326 rs5988 hCV31360339 rs4352723 0.51 0.9 1 hCV11972326 rs5988 hCV31360343 rs13203052 0.51 0.9 1 hCV11972326 rs5988 hCV31360344 rs4960170 0.51 0.9 1 hCV11972326 rs5988 hCV31360346 rs13220642 0.51 0.9 1 hCV11972326 rs5988 hCV31360347 rs13193648 0.51 0.9 1 hCV11972326 rs5988 hCV31360444 rs12181800 0.51 0.9 0.9527 hCV11972326 rs5988 hDV77006766 rs4463306 0.51 0.9 1 hCV11972326 rs5988 hDV77023919 rs4607478 0.51 0.9 1 hCV12020339 rs4531 hCV31083062 rs10993947 0.51 0.9 1 hCV1243283 rs1716 hCV1022603 rs220462 0.51 0.9 1 hCV1243283 rs1716 hCV11679326 rs2976234 0.51 0.9 0.9342 hCV1243283 rs1716 hCV1243284 rs2915555 0.51 0.9 1 hCV1243283 rs1716 hCV3211391 rs220461 0.51 0.9 0.9337 hCV1253630 rs2071307 hCV1253631 rs2239691 0.51 0.9 0.9801 hCV1253630 rs2071307 hCV1253643 rs868005 0.51 0.9 1 hCV1253630 rs2071307 hCV1253666 rs6971698 0.51 0.9 0.9259 hCV1323634 rs287475 hCV1323632 rs287479 0.51 0.9 1 hCV1323634 rs287475 hCV1323635 rs287474 0.51 0.9 1 hCV1323634 rs287475 hCV1323659 rs287360 0.51 0.9 0.9252 hCV1323634 rs287475 hCV1323680 rs12585011 0.51 0.9 0.9616 hCV1323634 rs287475 hCV1323684 rs287347 0.51 0.9 0.9616 hCV1323634 rs287475 hCV1323696 rs11842785 0.51 0.9 0.9608 hCV1323634 rs287475 hCV1323700 rs6562535 0.51 0.9 0.9567 hCV1323634 rs287475 hCV1323701 rs7330307 0.51 0.9 0.96 hCV1323634 rs287475 hCV1323702 rs7329795 0.51 0.9 0.96 hCV1323634 rs287475 hCV32085644 rs12585431 0.51 0.9 0.9616 hCV1323634 rs287475 hCV32085645 rs11842784 0.51 0.9 0.9608 hCV1323634 rs287475 hCV615776 rs287476 0.51 0.9 0.9166 hCV1323634 rs287475 hCV615780 rs287439 0.51 0.9 0.9166 hCV1323669 rs287354 hCV1323632 rs287479 0.51 0.9 0.9244 hCV1323669 rs287354 hCV1323635 rs287474 0.51 0.9 0.9244 hCV1323669 rs287354 hCV1323659 rs287360 0.51 0.9 0.9234 hCV1323669 rs287354 hCV1323670 rs167000 0.51 0.9 0.9407 hCV1323669 rs287354 hCV1323673 rs287352 0.51 0.9 0.98 hCV1323669 rs287354 hCV1323678 rs287350 0.51 0.9 0.9796 hCV1323669 rs287354 hCV1323680 rs12585011 0.51 0.9 0.9617 hCV1323669 rs287354 hCV1323684 rs287347 0.51 0.9 0.9617 hCV1323669 rs287354 hCV1323686 rs2039578 0.51 0.9 0.98 hCV1323669 rs287354 hCV1323696 rs11842785 0.51 0.9 0.9609 hCV1323669 rs287354 hCV1323700 rs6562535 0.51 0.9 0.9568 hCV1323669 rs287354 hCV1323701 rs7330307 0.51 0.9 0.96 hCV1323669 rs287354 hCV1323702 rs7329795 0.51 0.9 0.96 hCV1323669 rs287354 hCV1323703 rs17641312 0.51 0.9 0.9395 hCV1323669 rs287354 hCV1323704 rs8002457 0.51 0.9 0.9401 hCV1323669 rs287354 hCV32085644 rs12585431 0.51 0.9 0.9617 hCV1323669 rs287354 hCV32085645 rs11842784 0.51 0.9 0.9609 hCV1323669 rs287354 hCV615776 rs287476 0.51 0.9 0.9408 hCV1323669 rs287354 hCV615780 rs287439 0.51 0.9 0.9408 hCV1323669 rs287354 hCV7597674 rs287356 0.51 0.9 0.98 hCV1345898 rs2230804 hCV11753633 rs7923726 0.51 0.9 1 hCV1345898 rs2230804 hCV1345851 rs2270961 0.51 0.9 0.981 hCV1345898 rs2230804 hCV1345862 rs6584354 0.51 0.9 0.9619 hCV1345898 rs2230804 hCV1345912 rs7909855 0.51 0.9 0.9621 hCV1345898 rs2230804 hCV1858698 rs3818411 0.51 0.9 0.981 hCV1345898 rs2230804 hCV25592811 rs4919438 0.51 0.9 0.981 hCV1345898 rs2230804 hCV29348491 rs7922807 0.51 0.9 0.9619 hCV1345898 rs2230804 hCV29348492 rs7079072 0.51 0.9 0.9649 hCV1345898 rs2230804 hCV31980317 rs12254005 0.51 0.9 1 hCV1345898 rs2230804 hCV31980340 rs12242503 0.51 0.9 0.9619 hCV1345898 rs2230804 hCV31980399 rs12269373 0.51 0.9 0.981 hCV1361979 rs25683 hCV11414348 rs13202042 0.51 0.9 0.9812 hCV1361979 rs25683 hCV1361961 rs3818299 0.51 0.9 0.9812 hCV1361979 rs25683 hCV1361978 rs11751480 0.51 0.9 0.9621 hCV1361979 rs25683 hCV1361983 rs13194896 0.51 0.9 1 hCV1361979 rs25683 hCV1361988 rs3798211 0.51 0.9 0.9628 hCV1361979 rs25683 hCV1362003 rs1440 0.51 0.9 0.9812 hCV1361979 rs25683 hCV15818677 rs2842970 0.51 0.9 0.9648 hCV1361979 rs25683 hCV15818688 rs2842975 0.51 0.9 0.9648 hCV1361979 rs25683 hCV15818690 rs2842972 0.51 0.9 0.9807 hCV1361979 rs25683 hCV16179956 rs2273828 0.51 0.9 0.9812 hCV1361979 rs25683 hCV16191216 rs2295899 0.51 0.9 0.9812 hCV1361979 rs25683 hCV16288760 rs2758311 0.51 0.9 0.9635 hCV1361979 rs25683 hCV8699839 rs927450 0.51 0.9 0.9812 hCV1375141 rs1881420 hCV11167501 rs12619135 0.51 0.9 1 hCV1375141 rs1881420 hCV1375138 rs13428329 0.51 0.9 1 hCV1375141 rs1881420 hCV1375139 rs4666172 0.51 0.9 0.9054 hCV1375141 rs1881420 hCV1375144 rs2278879 0.51 0.9 1 hCV1375141 rs1881420 hCV27505984 rs3820712 0.51 0.9 0.9054 hCV1375141 rs1881420 hCV27513883 rs3768672 0.51 0.9 1 hCV1375141 rs1881420 hCV30109305 rs4666176 0.51 0.9 0.9054 hCV1375141 rs1881420 hCV32191953 rs13386033 0.51 0.9 0.9124 hCV1375141 rs1881420 hCV9531551 rs1026277 0.51 0.9 1 hCV1463112 rs3763608 hCV11765753 rs3793456 0.51 0.763750033 0.827 hCV1463112 rs3763608 hCV1463244 rs3793465 0.51 0.763750033 0.8333 hCV1463112 rs3763608 hCV1463252 rs3793461 0.51 0.763750033 0.8591 hCV1463112 rs3763608 hCV15761059 rs2309393 0.51 0.763750033 0.8333 hCV1463112 rs3763608 hCV26566199 rs3793467 0.51 0.763750033 0.8591 hCV1463112 rs3763608 hCV28008078 rs4745543 0.51 0.763750033 1 hCV1463112 rs3763608 hCV30586985 rs10126006 0.51 0.763750033 0.8497 hCV1463112 rs3763608 hCV31363797 rs11145043 0.51 0.763750033 0.7954 hCV1463112 rs3763608 hCV31363840 rs7875693 0.51 0.763750033 0.7758 hCV1463112 rs3763608 hCV31363841 rs7849347 0.51 0.763750033 0.792 hCV1463222 rs4744808 hCV11373123 rs1984003 0.51 0.343783224 1 hCV1463222 rs4744808 hCV11761245 rs7043149 0.51 0.343783224 0.3997 hCV1463222 rs4744808 hCV11765727 rs10781379 0.51 0.343783224 1 hCV1463222 rs4744808 hCV11765729 rs7875659 0.51 0.343783224 1 hCV1463222 rs4744808 hCV11765753 rs3793456 0.51 0.343783224 0.7223 hCV1463222 rs4744808 hCV1463101 rs7871596 0.51 0.343783224 0.4845 hCV1463222 rs4744808 hCV1463112 rs3763608 0.51 0.343783224 0.5342 hCV1463222 rs4744808 hCV1463185 rs953588 0.51 0.343783224 0.5193 hCV1463222 rs4744808 hCV1463197 rs6560551 0.51 0.343783224 0.7657 hCV1463222 rs4744808 hCV1463216 rs4745581 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463217 rs4745580 0.51 0.343783224 0.7657 hCV1463222 rs4744808 hCV1463218 rs1984004 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463223 rs4744807 0.51 0.343783224 0.7609 hCV1463222 rs4744808 hCV1463225 rs4745577 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463226 rs10890 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463229 rs7861997 0.51 0.343783224 0.7996 hCV1463222 rs4744808 hCV1463231 rs7870295 0.51 0.343783224 0.7657 hCV1463222 rs4744808 hCV1463232 rs9314854 0.51 0.343783224 1 hCV1463222 rs4744808 hCV1463235 rs2498430 0.51 0.343783224 0.4988 hCV1463222 rs4744808 hCV1463244 rs3793465 0.51 0.343783224 0.6837 hCV1463222 rs4744808 hCV1463247 rs3829064 0.51 0.343783224 0.5777 hCV1463222 rs4744808 hCV1463251 rs2498434 0.51 0.343783224 0.4995 hCV1463222 rs4744808 hCV1463252 rs3793461 0.51 0.343783224 0.6777 hCV1463222 rs4744808 hCV1463256 rs2309394 0.51 0.343783224 0.4563 hCV1463222 rs4744808 hCV15761059 rs2309393 0.51 0.343783224 0.6837 hCV1463222 rs4744808 hCV15892414 rs2498431 0.51 0.343783224 0.4988 hCV1463222 rs4744808 hCV15892430 rs2498433 0.51 0.343783224 0.3691 hCV1463222 rs4744808 hCV25609765 rs3829062 0.51 0.343783224 0.4563 hCV1463222 rs4744808 hCV26566199 rs3793467 0.51 0.343783224 0.6777 hCV1463222 rs4744808 hCV26566299 rs10869821 0.51 0.343783224 1 hCV1463222 rs4744808 hCV27517372 rs3793457 0.51 0.343783224 0.5504 hCV1463222 rs4744808 hCV27996874 rs4745701 0.51 0.343783224 0.3878 hCV1463222 rs4744808 hCV28008078 rs4745543 0.51 0.343783224 0.5597 hCV1463222 rs4744808 hCV28035790 rs4744811 0.51 0.343783224 0.7505 hCV1463222 rs4744808 hCV29861776 rs9411171 0.51 0.343783224 0.5777 hCV1463222 rs4744808 hCV30586985 rs10126006 0.51 0.343783224 0.6289 hCV1463222 rs4744808 hCV31363797 rs11145043 0.51 0.343783224 0.722 hCV1463222 rs4744808 hCV31363840 rs7875693 0.51 0.343783224 0.6922 hCV1463222 rs4744808 hCV31363841 rs7849347 0.51 0.343783224 0.7494 hCV1463222 rs4744808 hCV31363869 rs11145070 0.51 0.343783224 1 hCV1463222 rs4744808 hCV31363888 rs7859021 0.51 0.343783224 1 hCV1463222 rs4744808 hCV31363984 rs7855905 0.51 0.343783224 0.6837 hCV1463222 rs4744808 hCV31364141 rs11145460 0.51 0.343783224 0.3887 hCV1463222 rs4744808 hCV320569 rs9411170 0.51 0.343783224 0.444 hCV1463222 rs4744808 hCV8785184 rs1411676 0.51 0.343783224 1 hCV1463222 rs4744808 hCV8785185 rs1411675 0.51 0.343783224 1 hCV1463222 rs4744808 hCV9333267 rs1045632 0.51 0.343783224 1 hCV1463222 rs4744808 hDV71871695 rs7047274 0.51 0.343783224 0.4858 hCV1488444 rs10164405 hCV1488443 rs10409390 0.51 0.9 0.9556 hCV1488444 rs10164405 hCV1488445 rs2020362 0.51 0.9 0.9556 hCV1488444 rs10164405 hCV1488457 rs1529736 0.51 0.9 0.915 hCV1488444 rs10164405 hCV27115656 rs17546075 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV27115659 rs10424169 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV27115660 rs10423958 0.51 0.9 0.9556 hCV1488444 rs10164405 hCV27115665 rs17628547 0.51 0.9 0.9556 hCV1488444 rs10164405 hCV27115673 rs7351092 0.51 0.9 0.9118 hCV1488444 rs10164405 hCV29999392 rs10405722 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV30197290 rs10405541 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV30467374 rs10402416 0.51 0.9 0.9755 hCV1488444 rs10164405 hCV3057588 rs12977165 0.51 0.9 0.9514 hCV1488444 rs10164405 hCV3057604 rs17628655 0.51 0.9 0.9035 hCV1488444 rs10164405 hDV70967049 rs17545436 0.51 0.9 0.9135 hCV1488444 rs10164405 hDV70967068 rs17545624 0.51 0.9 0.9278 hCV1488444 rs10164405 hDV70967114 rs17545970 0.51 0.9 0.9124 hCV1488444 rs10164405 hDV70979159 rs17628152 0.51 0.9 0.9755 hCV1488444 rs10164405 hDV70979177 rs17628232 0.51 0.9 0.9755 hCV1488444 rs10164405 hDV75173800 rs17628099 0.51 0.9 0.9088 hCV1489995 rs4013819 hCV1489958 rs1501572 0.51 0.9 0.9295 hCV1489995 rs4013819 hCV1489988 rs7036937 0.51 0.9 1 hCV1489995 rs4013819 hCV1489991 rs10968723 0.51 0.9 0.9618 hCV1489995 rs4013819 hCV1489993 rs2134110 0.51 0.9 1 hCV1489995 rs4013819 hCV1489996 rs10120379 0.51 0.9 0.9611 hCV1489995 rs4013819 hCV1490005 rs7848307 0.51 0.9 0.9425 hCV1489995 rs4013819 hCV27089552 rs7868575 0.51 0.9 0.9431 hCV1489995 rs4013819 hCV29340958 rs7862374 0.51 0.9 0.9431 hCV1489995 rs4013819 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rs6502998 0.51 0.9 0.9426 hCV1552900 rs1126667 hCV9277205 rs6502999 0.51 0.9 0.9634 hCV15758290 rs6716834 hCV1533428 rs2544376 0.51 0.9 0.9765 hCV15758290 rs6716834 hCV8822225 rs2544377 0.51 0.9 1 hCV15758290 rs6716834 hCV8822233 rs861239 0.51 0.9 1 hCV15758290 rs6716834 hCV95255 rs2544381 0.51 0.9 0.9776 hCV15758290 rs6716834 hCV95256 rs2544380 0.51 0.9 1 hCV15851779 rs2230009 hCV12105879 rs2037962 0.51 0.9 1 hCV15851779 rs2230009 hCV15793665 rs3087418 0.51 0.9 1 hCV15851779 rs2230009 hCV25471760 rs3087409 0.51 0.9 1 hCV15851779 rs2230009 hCV25921517 rs3213197 0.51 0.9 1 hCV15851779 rs2230009 hCV25921527 rs4987239 0.51 0.9 1 hCV15851779 rs2230009 hCV27829132 rs11574175 0.51 0.9 1 hCV15851779 rs2230009 hCV31337210 rs11574400 0.51 0.9 0.9286 hCV15851779 rs2230009 hCV31674015 rs11574266 0.51 0.9 1 hCV15851779 rs2230009 hCV31674023 rs7829687 0.51 0.9 1 hCV15851779 rs2230009 hCV31674032 rs11574260 0.51 0.9 1 hCV15851779 rs2230009 hCV31674034 rs11574259 0.51 0.9 1 hCV15851779 rs2230009 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0.92 hCV25926771 rs4906321 hCV1292762 rs7152202 0.51 0.9 0.9227 hCV25926771 rs4906321 hCV16179592 rs2273699 0.51 0.9 0.96 hCV25926771 rs4906321 hCV26352257 rs11621037 0.51 0.9 0.9227 hCV25926771 rs4906321 hCV29078396 rs7158822 0.51 0.9 0.9199 hCV25926771 rs4906321 hCV31068323 rs12898029 0.51 0.9 0.9616 hCV25926771 rs4906321 hCV31068332 rs7158144 0.51 0.9 0.9057 hCV25926771 rs4906321 hCV8901411 rs1028613 0.51 0.9 0.9226 hCV25927459 rs3798221 hCV103951 rs6455688 0.51 0.47241724 0.4725 hCV25927459 rs3798221 hCV103952 rs6923877 0.51 0.47241724 0.4725 hCV25927459 rs3798221 hCV11285578 rs6926458 0.51 0.47241724 0.7323 hCV25927459 rs3798221 hCV26272388 rs7770685 0.51 0.47241724 0.7365 hCV25927459 rs3798221 hCV27422538 rs6940254 0.51 0.47241724 0.6129 hCV25927459 rs3798221 hCV27422565 rs13202636 0.51 0.47241724 0.7365 hCV25927459 rs3798221 hCV31882494 rs12175867 0.51 0.47241724 0.6129 hCV25927459 rs3798221 hCV3201490 rs1321195 0.51 0.47241724 0.6526 hCV25927459 rs3798221 hCV3201495 rs1367210 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hCV3211566 rs930181 0.51 0.9 0.9591 hCV25942539 rs2401751 hCV3211568 rs816075 0.51 0.9 1 hCV25942539 rs2401751 hCV9595827 rs845757 0.51 0.9 0.9591 hCV25942539 rs2401751 hCV9595840 rs816072 0.51 0.9 1 hCV25942539 rs2401751 hCV9595849 rs1152376 0.51 0.9 0.9793 hCV25942539 rs2401751 hCV9595856 rs816069 0.51 0.9 0.9586 hCV25942539 rs2401751 hCV9595863 rs1344747 0.51 0.9 0.9596 hCV26000635 rs7020782 hCV31783431 rs6478232 0.51 0.9 0.959 hCV26000635 rs7020782 hCV7594415 rs912214 0.51 0.9 0.9782 hCV260164 rs6754295 hCV1026586 rs673548 0.51 0.9 0.9441 hCV260164 rs6754295 hCV11168524 rs6544366 0.51 0.9 1 hCV260164 rs6754295 hCV11168530 rs6728178 0.51 0.9 1 hCV260164 rs6754295 hCV27912761 rs4564803 0.51 0.9 1 hCV260164 rs6754295 hCV29011391 rs7557067 0.51 0.9 1 hCV260164 rs6754295 hCV30455594 rs10184054 0.51 0.9 1 hCV260164 rs6754295 hCV30847428 rs11902417 0.51 0.9 1 hCV260164 rs6754295 hCV3216558 rs676210 0.51 0.9 0.9442 hCV260164 rs6754295 hCV7615376 rs1042034 0.51 0.9 0.9169 hCV2632070 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0.681759041 0.8732 hCV26660340 rs4968246 hCV7451308 rs1638446 0.51 0.681759041 0.756 hCV26683367 rs9894300 hCV11627552 rs2316667 0.51 0.60059725 0.9066 hCV26683367 rs9894300 hCV1718966 rs4968305 0.51 0.60059725 0.9072 hCV26683367 rs9894300 hCV26683368 rs2004580 0.51 0.60059725 0.8193 hCV26683367 rs9894300 hCV29195269 rs7221042 0.51 0.60059725 0.6383 hCV26683367 rs9894300 hCV30515746 rs10491149 0.51 0.60059725 0.6383 hCV26683367 rs9894300 hCV31479380 rs4520895 0.51 0.60059725 0.8206 hCV26683367 rs9894300 hDV70590478 rs9897338 0.51 0.60059725 0.8206 hCV26683367 rs9894300 hDV70751669 rs16941353 0.51 0.60059725 0.6383 hCV26683367 rs9894300 hDV70977122 rs17616652 0.51 0.60059725 0.6395 hCV26683367 rs9894300 hDV70987720 rs17676978 0.51 0.60059725 0.6383 hCV26683367 rs9894300 hDV75285090 rs2667804 0.51 0.60059725 0.9072 hCV26683368 rs2004580 hCV11627552 rs2316667 0.51 0.600149065 0.8315 hCV26683368 rs2004580 hCV1718966 rs4968305 0.51 0.600149065 0.9076 hCV26683368 rs2004580 hCV26683367 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hCV9306688 rs4743762 0.51 0.9 0.9603 hCV27422538 rs6940254 hCV11226249 rs6415085 0.51 0.459494331 0.5362 hCV27422538 rs6940254 hCV11285578 rs6926458 0.51 0.459494331 1 hCV27422538 rs6940254 hCV11846435 rs6929299 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hCV1550866 rs6932014 0.51 0.459494331 0.5362 hCV27422538 rs6940254 hCV243055 rs10945682 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hCV249895 rs7771129 0.51 0.459494331 0.5362 hCV27422538 rs6940254 hCV249898 rs9456552 0.51 0.459494331 0.55 hCV27422538 rs6940254 hCV25927459 rs3798221 0.51 0.459494331 0.6129 hCV27422538 rs6940254 hCV26272388 rs7770685 0.51 0.459494331 1 hCV27422538 rs6940254 hCV26272389 rs7760585 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hCV27422546 rs7761377 0.51 0.459494331 0.5504 hCV27422538 rs6940254 hCV27422547 rs6455696 0.51 0.459494331 0.5336 hCV27422538 rs6940254 hCV27422554 rs6923917 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hCV27422556 rs9355814 0.51 0.459494331 0.5659 hCV27422538 rs6940254 hCV27422557 rs9355813 0.51 0.459494331 0.5875 hCV27422538 rs6940254 hCV27422565 rs13202636 0.51 0.459494331 1 hCV27422538 rs6940254 hCV29709361 rs9365179 0.51 0.459494331 0.5152 hCV27422538 rs6940254 hCV29817515 rs9355817 0.51 0.459494331 0.51 hCV27422538 rs6940254 hCV29934611 rs9295130 0.51 0.459494331 0.5291 hCV27422538 rs6940254 hCV305046 rs6902102 0.51 0.459494331 0.5232 hCV27422538 rs6940254 hCV31882494 rs12175867 0.51 0.459494331 1 hCV27422538 rs6940254 hCV3201490 rs1321195 0.51 0.459494331 0.6 hCV27422538 rs6940254 hCV3201495 rs1367210 0.51 0.459494331 0.6129 hCV27422538 rs6940254 hCV3201497 rs1321196 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hCV8701273 rs783148 0.51 0.459494331 0.6 hCV27422538 rs6940254 hCV8710154 rs1569933 0.51 0.459494331 0.5291 hCV27422538 rs6940254 hCV8710161 rs1740428 0.51 0.459494331 0.5349 hCV27422538 rs6940254 hDV77235995 rs7746273 0.51 0.459494331 0.5362 hCV27462774 rs3127583 hCV16149755 rs2183470 0.51 0.708469605 1 hCV27462774 rs3127583 hCV16149755 rs2183470 0.51 0.756245335 1 hCV27462774 rs3127583 hCV27397381 rs3120149 0.51 0.708469605 1 hCV27462774 rs3127583 hCV27397381 rs3120149 0.51 0.756245335 1 hCV27462774 rs3127583 hCV27455194 rs3103347 0.51 0.708469605 0.9667 hCV27462774 rs3127583 hCV27455194 rs3103347 0.51 0.756245335 0.9667 hCV27462774 rs3127583 hCV27459536 rs3119310 0.51 0.708469605 0.776 hCV27462774 rs3127583 hCV27459536 rs3119310 0.51 0.756245335 0.776 hCV27462774 rs3127583 hCV27460663 rs3120137 0.51 0.708469605 0.9011 hCV27462774 rs3127583 hCV27460663 rs3120137 0.51 0.756245335 0.9011 hCV27462774 rs3127583 hCV27461119 rs3125056 0.51 0.708469605 0.8336 hCV27462774 rs3127583 hCV27461119 rs3125056 0.51 0.756245335 0.8336 hCV27462774 rs3127583 hCV27462007 rs3127578 0.51 0.708469605 0.776 hCV27462774 rs3127583 hCV27462007 rs3127578 0.51 0.756245335 0.776 hCV27462774 rs3127583 hCV27462671 rs3120139 0.51 0.708469605 1 hCV27462774 rs3127583 hCV27462671 rs3120139 0.51 0.756245335 1 hCV27462774 rs3127583 hCV27464241 rs3125052 0.51 0.708469605 1 hCV27462774 rs3127583 hCV27464241 rs3125052 0.51 0.756245335 1 hCV27462774 rs3127583 hCV27464790 rs3127591 0.51 0.708469605 0.9135 hCV27462774 rs3127583 hCV27464790 rs3127591 0.51 0.756245335 0.9135 hCV27462774 rs3127583 hCV30977815 rs3127597 0.51 0.708469605 0.8905 hCV27462774 rs3127583 hCV30977815 rs3127597 0.51 0.756245335 0.8905 hCV27462774 rs3127583 hCV30977817 rs3106168 0.51 0.708469605 1 hCV27462774 rs3127583 hCV30977817 rs3106168 0.51 0.756245335 1 hCV27462774 rs3127583 hCV30977839 rs3120140 0.51 0.708469605 0.8656 hCV27462774 rs3127583 hCV30977839 rs3120140 0.51 0.756245335 0.8656 hCV27462774 rs3127583 hCV30977855 rs3103350 0.51 0.708469605 1 hCV27462774 rs3127583 hCV30977855 rs3103350 0.51 0.756245335 1 hCV27462774 rs3127583 hCV31605072 rs12206585 0.51 0.708469605 1 hCV27462774 rs3127583 hCV31605072 rs12206585 0.51 0.756245335 1 hCV27462774 rs3127583 hCV31605081 rs12203303 0.51 0.708469605 0.8994 hCV27462774 rs3127583 hCV31605081 rs12203303 0.51 0.756245335 0.8994 hCV27462774 rs3127583 hCV32312668 rs3103349 0.51 0.708469605 1 hCV27462774 rs3127583 hCV32312668 rs3103349 0.51 0.756245335 1 hCV27462774 rs3127583 hDV71669191 rs3127586 0.51 0.708469605 1 hCV27462774 rs3127583 hDV71669191 rs3127586 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75428625 rs3106167 0.51 0.708469605 1 hCV27462774 rs3127583 hDV75428625 rs3106167 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75428626 rs3106170 0.51 0.708469605 1 hCV27462774 rs3127583 hDV75428626 rs3106170 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75428628 rs3106172 0.51 0.708469605 1 hCV27462774 rs3127583 hDV75428628 rs3106172 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75431938 rs3120151 0.51 0.708469605 1 hCV27462774 rs3127583 hDV75431938 rs3120151 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75433616 rs3125049 0.51 0.708469605 0.9278 hCV27462774 rs3127583 hDV75433616 rs3125049 0.51 0.756245335 0.9278 hCV27462774 rs3127583 hDV75433617 rs3125050 0.51 0.708469605 1 hCV27462774 rs3127583 hDV75433617 rs3125050 0.51 0.756245335 1 hCV27462774 rs3127583 hDV75433619 rs3125055 0.51 0.708469605 0.7337 hCV27480853 rs3766430 hCV2431627 rs646534 0.51 0.9 0.9437 hCV27480853 rs3766430 hCV27498227 rs3766431 0.51 0.9 0.9805 hCV27480853 rs3766430 hCV27498228 rs3766436 0.51 0.9 0.9643 hCV27480853 rs3766430 hCV27924561 rs4927080 0.51 0.9 0.9264 hCV27480853 rs3766430 hCV29234422 rs3766437 0.51 0.9 0.9643 hCV2762168 rs3939286 hCV12096527 rs1888909 0.51 0.9 0.9767 hCV2762168 rs3939286 hCV12096531 rs928413 0.51 0.9 0.9767 hCV2762168 rs3939286 hCV16108911 rs2095044 0.51 0.9 0.9616 hCV2762168 rs3939286 hCV16225421 rs2381416 0.51 0.9 0.9252 hCV2762168 rs3939286 hCV31940459 rs7848215 0.51 0.9 0.9252 hCV2762168 rs3939286 hCV8785827 rs992969 0.51 0.9 1 hCV2769554 rs1805010 hCV2769561 rs3024548 0.51 0.9 1 hCV2769554 rs1805010 hCV2769568 rs3024530 0.51 0.9 0.926 hCV2781953 rs6021931 hCV11182690 rs13045199 0.51 0.9 0.9391 hCV2781953 rs6021931 hCV2487050 rs17806278 0.51 0.9 0.9391 hCV2781953 rs6021931 hCV2487054 rs13043303 0.51 0.9 1 hCV2781953 rs6021931 hCV2487070 rs6091546 0.51 0.9 1 hCV2781953 rs6021931 hCV2487071 rs1473705 0.51 0.9 1 hCV2781953 rs6021931 hCV2487073 rs17806379 0.51 0.9 0.9393 hCV2781953 rs6021931 hCV2487087 rs13037630 0.51 0.9 1 hCV2781953 rs6021931 hCV2516638 rs13037010 0.51 0.9 0.942 hCV2781953 rs6021931 hCV2781950 rs6096949 0.51 0.9 1 hCV2781953 rs6021931 hCV2781958 rs6096956 0.51 0.9 0.9694 hCV2781953 rs6021931 hCV2781970 rs17806224 0.51 0.9 1 hCV2781953 rs6021931 hCV31734434 rs13039375 0.51 0.9 1 hCV2781953 rs6021931 hCV31734442 rs13039956 0.51 0.9 1 hCV2781953 rs6021931 hDV71605793 rs17203653 0.51 0.9 1 hCV27884601 rs4908776 hCV1188731 rs4908514 0.51 0.900202572 1 hCV27884601 rs4908776 hCV1188735 rs10864366 0.51 0.900202572 1 hCV27884601 rs4908776 hCV27157507 rs6664000 0.51 0.900202572 1 hCV27884601 rs4908776 hCV27157524 rs6577531 0.51 0.900202572 0.9351 hCV27884601 rs4908776 hCV28023091 rs4908773 0.51 0.900202572 1 hCV27884601 rs4908776 hCV29368919 rs4908513 0.51 0.900202572 1 hCV27884601 rs4908776 hCV29873524 rs7533113 0.51 0.900202572 1 hCV27884601 rs4908776 hCV29945430 rs7517436 0.51 0.900202572 1 hCV27884601 rs4908776 hCV30035535 rs7518204 0.51 0.900202572 1 hCV27884601 rs4908776 hCV32055527 rs10864364 0.51 0.900202572 1 hCV27884601 rs4908776 hCV32055579 rs6577522 0.51 0.900202572 1 hCV27884601 rs4908776 hCV32055595 rs6577524 0.51 0.900202572 1 hCV27884601 rs4908776 hCV32055596 rs6577525 0.51 0.900202572 1 hCV27884601 rs4908776 hCV32055637 rs6577532 0.51 0.900202572 0.9312 hCV27884601 rs4908776 hCV8823713 rs1472228 0.51 0.900202572 1 hCV27958354 rs4908762 hCV29873526 rs6697997 0.51 0.969446018 1 hCV27958354 rs4908762 hCV3086998 rs7530863 0.51 0.969446018 1 hCV27958354 rs4908762 hCV3087000 rs1463055 0.51 0.969446018 1 hCV27958354 rs4908762 hCV3087003 rs6577500 0.51 0.969446018 1 hCV27958354 rs4908762 hCV3087015 rs11121198 0.51 0.969446018 1 hCV27958354 rs4908762 hCV32055548 rs11121197 0.51 0.969446018 1 hCV27958354 rs4908762 hCV32055677 rs10864355 0.51 0.969446018 1 hCV27958354 rs4908762 hCV529178 rs301811 0.51 0.969446018 1 hCV27958354 rs4908762 hCV597227 rs301809 0.51 0.969446018 1 hCV27958354 rs4908762 hCV597229 rs301785 0.51 0.969446018 1 hCV27958354 rs4908762 hCV8824288 rs910582 0.51 0.969446018 1 hCV27958354 rs4908762 hCV8881161 rs926951 0.51 0.969446018 1 hCV28008078 rs4745543 hCV11765753 rs3793456 0.51 0.766415386 0.8388 hCV28008078 rs4745543 hCV1463112 rs3763608 0.51 0.766415386 1 hCV28008078 rs4745543 hCV1463244 rs3793465 0.51 0.766415386 0.827 hCV28008078 rs4745543 hCV1463252 rs3793461 0.51 0.766415386 0.8689 hCV28008078 rs4745543 hCV15761059 rs2309393 0.51 0.766415386 0.827 hCV28008078 rs4745543 hCV26566199 rs3793467 0.51 0.766415386 0.8689 hCV28008078 rs4745543 hCV30586985 rs10126006 0.51 0.766415386 0.8573 hCV28008078 rs4745543 hCV31363797 rs11145043 0.51 0.766415386 0.792 hCV28008078 rs4745543 hCV31363840 rs7875693 0.51 0.766415386 0.7884 hCV28008078 rs4745543 hCV31363841 rs7849347 0.51 0.766415386 0.8065 hCV28008078 rs4745543 hCV31363984 rs7855905 0.51 0.766415386 0.792 hCV28023091 rs4908773 hCV11398434 rs1812457 0.51 0.495466362 0.7979 hCV28023091 rs4908773 hCV11398437 rs1817367 0.51 0.495466362 0.6548 hCV28023091 rs4908773 hCV11675962 rs10746481 0.51 0.495466362 0.8704 hCV28023091 rs4908773 hCV1188659 rs3820037 0.51 0.495466362 0.5447 hCV28023091 rs4908773 hCV1188660 rs6660137 0.51 0.495466362 0.5538 hCV28023091 rs4908773 hCV1188664 rs2765511 0.51 0.495466362 0.6126 hCV28023091 rs4908773 hCV1188665 rs2781060 0.51 0.495466362 0.6354 hCV28023091 rs4908773 hCV1188676 rs11121247 0.51 0.495466362 0.5538 hCV28023091 rs4908773 hCV1188731 rs4908514 0.51 0.495466362 1 hCV28023091 rs4908773 hCV1188735 rs10864366 0.51 0.495466362 1 hCV28023091 rs4908773 hCV12040675 rs2038904 0.51 0.495466362 0.6126 hCV28023091 rs4908773 hCV15882429 rs2289732 0.51 0.495466362 0.6247 hCV28023091 rs4908773 hCV15932991 rs2781067 0.51 0.495466362 0.6188 hCV28023091 rs4908773 hCV15932992 rs2781068 0.51 0.495466362 0.6121 hCV28023091 rs4908773 hCV27157507 rs6664000 0.51 0.495466362 1 hCV28023091 rs4908773 hCV27157524 rs6577531 0.51 0.495466362 0.9314 hCV28023091 rs4908773 hCV2741759 rs11121179 0.51 0.495466362 0.6713 hCV28023091 rs4908773 hCV27474399 rs3753275 0.51 0.495466362 0.5807 hCV28023091 rs4908773 hCV27884601 rs4908776 0.51 0.495466362 1 hCV28023091 rs4908773 hCV27958354 rs4908762 0.51 0.495466362 0.6717 hCV28023091 rs4908773 hCV29368919 rs4908513 0.51 0.495466362 1 hCV28023091 rs4908773 hCV2943451 rs902355 0.51 0.495466362 0.7098 hCV28023091 rs4908773 hCV2943853 rs301793 0.51 0.495466362 0.6247 hCV28023091 rs4908773 hCV2966436 rs11121174 0.51 0.495466362 0.6247 hCV28023091 rs4908773 hCV2966437 rs11580417 0.51 0.495466362 0.6247 hCV28023091 rs4908773 hCV2966441 rs6684863 0.51 0.495466362 0.6247 hCV28023091 rs4908773 hCV2966444 rs11121171 0.51 0.495466362 0.6727 hCV28023091 rs4908773 hCV29819064 rs6698079 0.51 0.495466362 0.7458 hCV28023091 rs4908773 hCV2987250 rs301810 0.51 0.495466362 0.5105 hCV28023091 rs4908773 hCV29873524 rs7533113 0.51 0.495466362 1 hCV28023091 rs4908773 hCV29873526 rs6697997 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV29945430 rs7517436 0.51 0.495466362 1 hCV28023091 rs4908773 hCV30035535 rs7518204 0.51 0.495466362 1 hCV28023091 rs4908773 hCV30125699 rs4581300 0.51 0.495466362 0.6067 hCV28023091 rs4908773 hCV30143725 rs6690050 0.51 0.495466362 0.7437 hCV28023091 rs4908773 hCV30467730 rs6702457 0.51 0.495466362 0.8704 hCV28023091 rs4908773 hCV3086930 rs6658881 0.51 0.495466362 0.8213 hCV28023091 rs4908773 hCV3086932 rs7533442 0.51 0.495466362 0.8213 hCV28023091 rs4908773 hCV3086950 rs4908771 0.51 0.495466362 0.8704 hCV28023091 rs4908773 hCV3086961 rs6703577 0.51 0.495466362 0.7188 hCV28023091 rs4908773 hCV3086971 rs6679948 0.51 0.495466362 0.7979 hCV28023091 rs4908773 hCV3086972 rs6688329 0.51 0.495466362 0.8568 hCV28023091 rs4908773 hCV3086998 rs7530863 0.51 0.495466362 0.6717 hCV28023091 rs4908773 hCV3087000 rs1463055 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV3087003 rs6577500 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV3087015 rs11121198 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV3087016 rs2297867 0.51 0.495466362 0.6499 hCV28023091 rs4908773 hCV32055284 rs12079653 0.51 0.495466362 0.6676 hCV28023091 rs4908773 hCV32055470 rs6577506 0.51 0.495466362 0.7188 hCV28023091 rs4908773 hCV32055474 rs10864359 0.51 0.495466362 0.6717 hCV28023091 rs4908773 hCV32055477 rs10779705 0.51 0.495466362 0.7979 hCV28023091 rs4908773 hCV32055527 rs10864364 0.51 0.495466362 1 hCV28023091 rs4908773 hCV32055548 rs11121197 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV32055579 rs6577522 0.51 0.495466362 1 hCV28023091 rs4908773 hCV32055595 rs6577524 0.51 0.495466362 1 hCV28023091 rs4908773 hCV32055596 rs6577525 0.51 0.495466362 1 hCV28023091 rs4908773 hCV32055625 rs6678590 0.51 0.495466362 0.8645 hCV28023091 rs4908773 hCV32055637 rs6577532 0.51 0.495466362 0.8301 hCV28023091 rs4908773 hCV32055662 rs6677249 0.51 0.495466362 0.645 hCV28023091 rs4908773 hCV32055677 rs10864355 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV529178 rs301811 0.51 0.495466362 0.6949 hCV28023091 rs4908773 hCV529182 rs301800 0.51 0.495466362 0.6998 hCV28023091 rs4908773 hCV597227 rs301809 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV597229 rs301785 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV877241 rs301788 0.51 0.495466362 0.6713 hCV28023091 rs4908773 hCV8823713 rs1472228 0.51 0.495466362 1 hCV28023091 rs4908773 hCV8824244 rs1006950 0.51 0.495466362 0.574 hCV28023091 rs4908773 hCV8824248 rs1543711 0.51 0.495466362 0.6126 hCV28023091 rs4908773 hCV8824288 rs910582 0.51 0.495466362 0.6952 hCV28023091 rs4908773 hCV8824394 rs1443929 0.51 0.495466362 0.6713 hCV28023091 rs4908773 hCV8824424 rs1058790 0.51 0.495466362 0.6727 hCV28023091 rs4908773 hCV8824425 rs1058791 0.51 0.495466362 0.6383 hCV28023091 rs4908773 hCV8881145 rs1038008 0.51 0.495466362 0.7979 hCV28023091 rs4908773 hCV8881146 rs1463054 0.51 0.495466362 0.8032 hCV28023091 rs4908773 hCV8881157 rs1535158 0.51 0.495466362 0.7979 hCV28023091 rs4908773 hCV8881161 rs926951 0.51 0.495466362 0.6717 hCV282793 rs11751605 hCV30977815 rs3127597 0.51 0.782580889 0.801 hCV28960526 rs6853079 hCV28960525 rs6532740 0.51 0.9 1 hCV28960526 rs6853079 hCV29480044 rs10516433 0.51 0.9 1 hCV28960526 rs6853079 hCV30454150 rs10516434 0.51 0.9 0.9309 hCV28960526 rs6853079 hCV30694936 rs6840610 0.51 0.9 1 hCV28960526 rs6853079 hDV70961198 rs17498778 0.51 0.9 1 hCV28960526 rs6853079 hDV70961229 rs17499015 0.51 0.9 0.9398 hCV28960526 rs6853079 hDV70969482 rs17564872 0.51 0.9 1 hCV28960526 rs6853079 hDV71951446 rs7689289 0.51 0.9 1 hCV28974083 rs8032553 hCV26066881 rs11629584 0.51 0.9 1 hCV28974083 rs8032553 hCV30732106 rs4556765 0.51 0.9 0.9647 hCV28974083 rs8032553 hCV31590435 rs11634571 0.51 0.9 0.9634 hCV29011391 rs7557067 hCV11168524 rs6544366 0.51 0.9 1 hCV29011391 rs7557067 hCV11168530 rs6728178 0.51 0.9 1 hCV29011391 rs7557067 hCV260164 rs6754295 0.51 0.9 1 hCV29011391 rs7557067 hCV27912761 rs4564803 0.51 0.9 1 hCV29011391 rs7557067 hCV30455594 rs10184054 0.51 0.9 1 hCV29011391 rs7557067 hCV30847428 rs11902417 0.51 0.9 1 hCV29135108 rs6743779 hCV2772191 rs10170608 0.51 0.9 0.9005 hCV2932115 rs5517 hCV1531092 rs3745522 0.51 0.9 0.9476 hCV2932115 rs5517 hCV29188580 rs3212820 0.51 0.9 1 hCV2932115 rs5517 hCV2932116 rs5519 0.51 0.9 1 hCV29322781 rs6921516 hCV103951 rs6455688 0.51 0.465336662 0.9792 hCV29322781 rs6921516 hCV103951 rs6455688 0.51 0.622712349 0.9792 hCV29322781 rs6921516 hCV103952 rs6923877 0.51 0.465336662 0.9792 hCV29322781 rs6921516 hCV103952 rs6923877 0.51 0.622712349 0.9792 hCV29322781 rs6921516 hCV11226249 rs6415085 0.51 0.465336662 0.7601 hCV29322781 rs6921516 hCV11226249 rs6415085 0.51 0.622712349 0.7601 hCV29322781 rs6921516 hCV11284288 rs9457946 0.51 0.465336662 1 hCV29322781 rs6921516 hCV11284288 rs9457946 0.51 0.622712349 1 hCV29322781 rs6921516 hCV11846435 rs6929299 0.51 0.465336662 0.8326 hCV29322781 rs6921516 hCV11846435 rs6929299 0.51 0.622712349 0.8326 hCV29322781 rs6921516 hCV1550866 rs6932014 0.51 0.465336662 0.7601 hCV29322781 rs6921516 hCV1550866 rs6932014 0.51 0.622712349 0.7601 hCV29322781 rs6921516 hCV1550871 rs9355295 0.51 0.465336662 1 hCV29322781 rs6921516 hCV1550871 rs9355295 0.51 0.622712349 1 hCV29322781 rs6921516 hCV207123 rs7771801 0.51 0.465336662 1 hCV29322781 rs6921516 hCV207123 rs7771801 0.51 0.622712349 1 hCV29322781 rs6921516 hCV207127 rs7453899 0.51 0.465336662 0.9795 hCV29322781 rs6921516 hCV207127 rs7453899 0.51 0.622712349 0.9795 hCV29322781 rs6921516 hCV207128 rs6455689 0.51 0.465336662 0.9184 hCV29322781 rs6921516 hCV207128 rs6455689 0.51 0.622712349 0.9184 hCV29322781 rs6921516 hCV243055 rs10945682 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV243055 rs10945682 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV249895 rs7771129 0.51 0.465336662 0.7601 hCV29322781 rs6921516 hCV249895 rs7771129 0.51 0.622712349 0.7601 hCV29322781 rs6921516 hCV249897 rs6913833 0.51 0.465336662 0.6796 hCV29322781 rs6921516 hCV249897 rs6913833 0.51 0.622712349 0.6796 hCV29322781 rs6921516 hCV249898 rs9456552 0.51 0.465336662 0.7704 hCV29322781 rs6921516 hCV249898 rs9456552 0.51 0.622712349 0.7704 hCV29322781 rs6921516 hCV25929408 rs7765781 0.51 0.465336662 1 hCV29322781 rs6921516 hCV25929408 rs7765781 0.51 0.622712349 1 hCV29322781 rs6921516 hCV25929478 rs7765803 0.51 0.465336662 0.9795 hCV29322781 rs6921516 hCV25929478 rs7765803 0.51 0.622712349 0.9795 hCV29322781 rs6921516 hCV26272389 rs7760585 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV26272389 rs7760585 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV27422546 rs7761377 0.51 0.465336662 0.722 hCV29322781 rs6921516 hCV27422546 rs7761377 0.51 0.622712349 0.722 hCV29322781 rs6921516 hCV27422547 rs6455696 0.51 0.465336662 0.7271 hCV29322781 rs6921516 hCV27422547 rs6455696 0.51 0.622712349 0.7271 hCV29322781 rs6921516 hCV27422554 rs6923917 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV27422554 rs6923917 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV27422556 rs9355814 0.51 0.465336662 0.7413 hCV29322781 rs6921516 hCV27422556 rs9355814 0.51 0.622712349 0.7413 hCV29322781 rs6921516 hCV27422557 rs9355813 0.51 0.465336662 0.767 hCV29322781 rs6921516 hCV27422557 rs9355813 0.51 0.622712349 0.767 hCV29322781 rs6921516 hCV27422575 rs6415084 0.51 0.465336662 0.4788 hCV29322781 rs6921516 hCV29546641 rs9365171 0.51 0.465336662 0.8819 hCV29322781 rs6921516 hCV29546641 rs9365171 0.51 0.622712349 0.8819 hCV29322781 rs6921516 hCV29709361 rs9365179 0.51 0.465336662 0.8171 hCV29322781 rs6921516 hCV29709361 rs9365179 0.51 0.622712349 0.8171 hCV29322781 rs6921516 hCV29817515 rs9355817 0.51 0.465336662 0.6883 hCV29322781 rs6921516 hCV29817515 rs9355817 0.51 0.622712349 0.6883 hCV29322781 rs6921516 hCV29934611 rs9295130 0.51 0.465336662 0.8152 hCV29322781 rs6921516 hCV29934611 rs9295130 0.51 0.622712349 0.8152 hCV29322781 rs6921516 hCV29998162 rs9457943 0.51 0.465336662 1 hCV29322781 rs6921516 hCV29998162 rs9457943 0.51 0.622712349 1 hCV29322781 rs6921516 hCV305046 rs6902102 0.51 0.465336662 0.7529 hCV29322781 rs6921516 hCV305046 rs6902102 0.51 0.622712349 0.7529 hCV29322781 rs6921516 hCV30574599 rs7770628 0.51 0.465336662 0.4698 hCV29322781 rs6921516 hCV3201494 rs1367209 0.51 0.465336662 0.7291 hCV29322781 rs6921516 hCV3201494 rs1367209 0.51 0.622712349 0.7291 hCV29322781 rs6921516 hCV3201497 rs1321196 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV3201497 rs1321196 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV8710154 rs1569933 0.51 0.465336662 0.8274 hCV29322781 rs6921516 hCV8710154 rs1569933 0.51 0.622712349 0.8274 hCV29322781 rs6921516 hCV8710161 rs1740428 0.51 0.465336662 0.8334 hCV29322781 rs6921516 hCV8710161 rs1740428 0.51 0.622712349 0.8334 hCV29322781 rs6921516 hCV8710162 rs1367211 0.51 0.465336662 0.7291 hCV29322781 rs6921516 hCV8710162 rs1367211 0.51 0.622712349 0.7291 hCV29322781 rs6921516 hDV77235995 rs7746273 0.51 0.465336662 0.6915 hCV29322781 rs6921516 hDV77235995 rs7746273 0.51 0.622712349 0.6915 hCV29368919 rs4908513 hCV11398434 rs1812457 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV11398437 rs1817367 0.51 0.496733059 0.7755 hCV29368919 rs4908513 hCV11675962 rs10746481 0.51 0.496733059 0.8774 hCV29368919 rs4908513 hCV1188659 rs3820037 0.51 0.496733059 0.5968 hCV29368919 rs4908513 hCV1188660 rs6660137 0.51 0.496733059 0.6126 hCV29368919 rs4908513 hCV1188664 rs2765511 0.51 0.496733059 0.6312 hCV29368919 rs4908513 hCV1188665 rs2781060 0.51 0.496733059 0.6541 hCV29368919 rs4908513 hCV1188676 rs11121247 0.51 0.496733059 0.6126 hCV29368919 rs4908513 hCV1188731 rs4908514 0.51 0.496733059 1 hCV29368919 rs4908513 hCV1188735 rs10864366 0.51 0.496733059 1 hCV29368919 rs4908513 hCV12040675 rs2038904 0.51 0.496733059 0.6312 hCV29368919 rs4908513 hCV15882429 rs2289732 0.51 0.496733059 0.6452 hCV29368919 rs4908513 hCV15932991 rs2781067 0.51 0.496733059 0.6396 hCV29368919 rs4908513 hCV15932992 rs2781068 0.51 0.496733059 0.6308 hCV29368919 rs4908513 hCV27157507 rs6664000 0.51 0.496733059 1 hCV29368919 rs4908513 hCV27157524 rs6577531 0.51 0.496733059 0.9353 hCV29368919 rs4908513 hCV27157546 rs11811795 0.51 0.496733059 0.5453 hCV29368919 rs4908513 hCV27157560 rs11121252 0.51 0.496733059 0.5135 hCV29368919 rs4908513 hCV2741759 rs11121179 0.51 0.496733059 0.6247 hCV29368919 rs4908513 hCV27884601 rs4908776 0.51 0.496733059 1 hCV29368919 rs4908513 hCV27958354 rs4908762 0.51 0.496733059 0.6952 hCV29368919 rs4908513 hCV28023091 rs4908773 0.51 0.496733059 1 hCV29368919 rs4908513 hCV2943451 rs902355 0.51 0.496733059 0.7273 hCV29368919 rs4908513 hCV2943853 rs301793 0.51 0.496733059 0.6452 hCV29368919 rs4908513 hCV2966436 rs11121174 0.51 0.496733059 0.6452 hCV29368919 rs4908513 hCV2966437 rs11580417 0.51 0.496733059 0.6452 hCV29368919 rs4908513 hCV2966441 rs6684863 0.51 0.496733059 0.6452 hCV29368919 rs4908513 hCV2966444 rs11121171 0.51 0.496733059 0.6911 hCV29368919 rs4908513 hCV29819064 rs6698079 0.51 0.496733059 0.7479 hCV29368919 rs4908513 hCV2987250 rs301810 0.51 0.496733059 0.5341 hCV29368919 rs4908513 hCV29873524 rs7533113 0.51 0.496733059 1 hCV29368919 rs4908513 hCV29873526 rs6697997 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV29945430 rs7517436 0.51 0.496733059 1 hCV29368919 rs4908513 hCV30035535 rs7518204 0.51 0.496733059 1 hCV29368919 rs4908513 hCV30125699 rs4581300 0.51 0.496733059 0.6952 hCV29368919 rs4908513 hCV30143725 rs6690050 0.51 0.496733059 0.7577 hCV29368919 rs4908513 hCV30467730 rs6702457 0.51 0.496733059 0.8774 hCV29368919 rs4908513 hCV3086930 rs6658881 0.51 0.496733059 0.8704 hCV29368919 rs4908513 hCV3086932 rs7533442 0.51 0.496733059 0.8704 hCV29368919 rs4908513 hCV3086950 rs4908771 0.51 0.496733059 0.8774 hCV29368919 rs4908513 hCV3086961 rs6703577 0.51 0.496733059 0.7979 hCV29368919 rs4908513 hCV3086971 rs6679948 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV3086972 rs6688329 0.51 0.496733059 0.8654 hCV29368919 rs4908513 hCV3086998 rs7530863 0.51 0.496733059 0.6952 hCV29368919 rs4908513 hCV3087000 rs1463055 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV3087003 rs6577500 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV3087015 rs11121198 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV3087016 rs2297867 0.51 0.496733059 0.6952 hCV29368919 rs4908513 hCV32055284 rs12079653 0.51 0.496733059 0.6858 hCV29368919 rs4908513 hCV32055470 rs6577506 0.51 0.496733059 0.7979 hCV29368919 rs4908513 hCV32055474 rs10864359 0.51 0.496733059 0.7979 hCV29368919 rs4908513 hCV32055477 rs10779705 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV32055527 rs10864364 0.51 0.496733059 1 hCV29368919 rs4908513 hCV32055548 rs11121197 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV32055579 rs6577522 0.51 0.496733059 1 hCV29368919 rs4908513 hCV32055595 rs6577524 0.51 0.496733059 1 hCV29368919 rs4908513 hCV32055596 rs6577525 0.51 0.496733059 1 hCV29368919 rs4908513 hCV32055625 rs6678590 0.51 0.496733059 0.879 hCV29368919 rs4908513 hCV32055637 rs6577532 0.51 0.496733059 0.9314 hCV29368919 rs4908513 hCV32055662 rs6677249 0.51 0.496733059 0.7437 hCV29368919 rs4908513 hCV32055677 rs10864355 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV529178 rs301811 0.51 0.496733059 0.7109 hCV29368919 rs4908513 hCV529182 rs301800 0.51 0.496733059 0.6732 hCV29368919 rs4908513 hCV597227 rs301809 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV597229 rs301785 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV877241 rs301788 0.51 0.496733059 0.6247 hCV29368919 rs4908513 hCV8823713 rs1472228 0.51 0.496733059 1 hCV29368919 rs4908513 hCV8824241 rs1325920 0.51 0.496733059 0.5423 hCV29368919 rs4908513 hCV8824244 rs1006950 0.51 0.496733059 0.6126 hCV29368919 rs4908513 hCV8824248 rs1543711 0.51 0.496733059 0.6312 hCV29368919 rs4908513 hCV8824288 rs910582 0.51 0.496733059 0.7112 hCV29368919 rs4908513 hCV8824394 rs1443929 0.51 0.496733059 0.6247 hCV29368919 rs4908513 hCV8824424 rs1058790 0.51 0.496733059 0.6911 hCV29368919 rs4908513 hCV8824425 rs1058791 0.51 0.496733059 0.6721 hCV29368919 rs4908513 hCV8881145 rs1038008 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV8881146 rs1463054 0.51 0.496733059 0.8042 hCV29368919 rs4908513 hCV8881157 rs1535158 0.51 0.496733059 0.8094 hCV29368919 rs4908513 hCV8881161 rs926951 0.51 0.496733059 0.6952 hCV29480044 rs10516433 hCV28960525 rs6532740 0.51 0.9 1 hCV29480044 rs10516433 hCV28960526 rs6853079 0.51 0.9 1 hCV29480044 rs10516433 hCV30454150 rs10516434 0.51 0.9 0.9309 hCV29480044 rs10516433 hCV30694936 rs6840610 0.51 0.9 1 hCV29480044 rs10516433 hDV70961198 rs17498778 0.51 0.9 1 hCV29480044 rs10516433 hDV70961229 rs17499015 0.51 0.9 0.9398 hCV29480044 rs10516433 hDV70969482 rs17564872 0.51 0.9 1 hCV29480044 rs10516433 hDV71951446 rs7689289 0.51 0.9 1 hCV2960489 rs3785889 hCV10293 rs3851786 0.51 0.784117293 0.8104 hCV2960489 rs3785889 hCV11623025 rs9898981 0.51 0.784117293 0.8121 hCV2960489 rs3785889 hCV11623029 rs2316330 0.51 0.784117293 0.8195 hCV2960489 rs3785889 hCV2275283 rs740617 0.51 0.784117293 0.7937 hCV2960489 rs3785889 hCV2592671 rs197926 0.51 0.784117293 0.8209 hCV2960489 rs3785889 hCV2592673 rs4968286 0.51 0.784117293 0.8591 hCV2960489 rs3785889 hCV2592677 rs736604 0.51 0.784117293 0.8209 hCV2960489 rs3785889 hCV2592681 rs17608961 0.51 0.784117293 0.8586 hCV2960489 rs3785889 hCV26660327 rs11869840 0.51 0.784117293 0.8578 hCV2960489 rs3785889 hCV29195266 rs3809854 0.51 0.784117293 0.8209 hCV2960489 rs3785889 hCV2959464 rs3760377 0.51 0.784117293 0.8591 hCV2960489 rs3785889 hCV2959466 rs6504622 0.51 0.784117293 0.8591 hCV2960489 rs3785889 hCV30299603 rs9889762 0.51 0.784117293 0.8398 hCV2960489 rs3785889 hCV31466218 rs11079745 0.51 0.784117293 0.8586 hCV2960489 rs3785889 hCV31466219 rs11652318 0.51 0.784117293 0.8195 hCV2960489 rs3785889 hCV7448063 rs736603 0.51 0.784117293 0.816 hCV2960489 rs3785889 hCV7451199 rs3851785 0.51 0.784117293 0.8195 hCV2960489 rs3785889 hCV7451217 rs1052586 0.51 0.784117293 0.8398 hCV29684678 rs10486788 hCV11811746 rs12669397 0.51 0.9 0.9583 hCV29684678 rs10486788 hCV2641110 rs6948282 0.51 0.9 0.9783 hCV29684678 rs10486788 hCV2641111 rs13239842 0.51 0.9 0.9783 hCV29684678 rs10486788 hCV2641141 rs13236237 0.51 0.9 0.9583 hCV29684678 rs10486788 hCV2641147 rs13234986 0.51 0.9 1 hCV29684678 rs10486788 hCV2641150 rs17169192 0.51 0.9 1 hCV29684678 rs10486788 hCV26518087 rs12699759 0.51 0.9 0.9783 hCV29684678 rs10486788 hCV31310415 rs12674430 0.51 0.9 1 hCV29684678 rs10486788 hCV31310435 rs10950592 0.51 0.9 0.9184 hCV29684678 rs10486788 hCV31310483 rs13230922 0.51 0.9 0.919 hCV29684678 rs10486788 hCV7603468 rs1299916 0.51 0.9 1 hCV29684678 rs10486788 hDV70913803 rs17169201 0.51 0.9 1 hCV29819064 rs6698079 hCV11398434 rs1812457 0.51 0.900593335 1 hCV29819064 rs6698079 hCV11398437 rs1817367 0.51 0.900593335 1 hCV29819064 rs6698079 hCV11675962 rs10746481 0.51 0.900593335 0.919 hCV29819064 rs6698079 hCV30143725 rs6690050 0.51 0.900593335 0.919 hCV29819064 rs6698079 hCV30467730 rs6702457 0.51 0.900593335 0.919 hCV29819064 rs6698079 hCV3086930 rs6658881 0.51 0.900593335 0.9184 hCV29819064 rs6698079 hCV3086932 rs7533442 0.51 0.900593335 0.9184 hCV29819064 rs6698079 hCV3086950 rs4908771 0.51 0.900593335 0.919 hCV29819064 rs6698079 hCV3086961 rs6703577 0.51 0.900593335 1 hCV29819064 rs6698079 hCV3086971 rs6679948 0.51 0.900593335 1 hCV29819064 rs6698079 hCV3086972 rs6688329 0.51 0.900593335 1 hCV29819064 rs6698079 hCV32055470 rs6577506 0.51 0.900593335 1 hCV29819064 rs6698079 hCV32055474 rs10864359 0.51 0.900593335 1 hCV29819064 rs6698079 hCV32055477 rs10779705 0.51 0.900593335 1 hCV29819064 rs6698079 hCV8881145 rs1038008 0.51 0.900593335 1 hCV29819064 rs6698079 hCV8881146 rs1463054 0.51 0.900593335 1 hCV29819064 rs6698079 hCV8881157 rs1535158 0.51 0.900593335 1 hCV2983035 rs9527026 hCV25611075 rs7997728 0.51 0.9 1 hCV2983035 rs9527026 hCV29426416 rs8000084 0.51 0.9 1 hCV2983035 rs9527026 hCV29426417 rs8001148 0.51 0.9 1 hCV2983035 rs9527026 hCV29426429 rs7986435 0.51 0.9 1 hCV2983035 rs9527026 hCV29676871 rs9527032 0.51 0.9 0.9428 hCV2983035 rs9527026 hCV29803144 rs7982726 0.51 0.9 1 hCV2983035 rs9527026 hCV2983036 rs9527025 0.51 0.9 1 hCV2983035 rs9527026 hCV2983037 rs9536314 0.51 0.9 1 hCV2983035 rs9527026 hCV2983038 rs9536313 0.51 0.9 1 hCV2983035 rs9527026 hCV2983040 rs9527024 0.51 0.9 1 hCV2983035 rs9527026 hCV29929821 rs9536239 0.51 0.9 1 hCV2983035 rs9527026 hCV30109848 rs9526990 0.51 0.9 1 hCV2983035 rs9527026 hCV30181994 rs9527022 0.51 0.9 1 hCV2983035 rs9527026 hCV30217619 rs9527023 0.51 0.9 1 hCV2983035 rs9527026 hCV30452057 rs9526992 0.51 0.9 0.9174 hCV2983035 rs9527026 hCV30469913 rs9536234 0.51 0.9 1 hCV2983035 rs9527026 hCV30487772 rs9526998 0.51 0.9 1 hCV2983035 rs9527026 hCV30560346 rs9527021 0.51 0.9 1 hCV2983035 rs9527026 hCV32231920 rs12020187 0.51 0.9 1 hCV2983035 rs9527026 hDV72067820 rs9536282 0.51 0.9 0.9674 hCV2983036 rs9527025 hCV25611075 rs7997728 0.51 0.9 1 hCV2983036 rs9527025 hCV29426416 rs8000084 0.51 0.9 1 hCV2983036 rs9527025 hCV29426417 rs8001148 0.51 0.9 1 hCV2983036 rs9527025 hCV29426429 rs7986435 0.51 0.9 1 hCV2983036 rs9527025 hCV29676871 rs9527032 0.51 0.9 0.9438 hCV2983036 rs9527025 hCV29803144 rs7982726 0.51 0.9 1 hCV2983036 rs9527025 hCV2983035 rs9527026 0.51 0.9 1 hCV2983036 rs9527025 hCV2983037 rs9536314 0.51 0.9 1 hCV2983036 rs9527025 hCV2983038 rs9536313 0.51 0.9 1 hCV2983036 rs9527025 hCV2983040 rs9527024 0.51 0.9 1 hCV2983036 rs9527025 hCV29929821 rs9536239 0.51 0.9 1 hCV2983036 rs9527025 hCV30109848 rs9526990 0.51 0.9 1 hCV2983036 rs9527025 hCV30181994 rs9527022 0.51 0.9 1 hCV2983036 rs9527025 hCV30217619 rs9527023 0.51 0.9 1 hCV2983036 rs9527025 hCV30452057 rs9526992 0.51 0.9 0.9184 hCV2983036 rs9527025 hCV30469913 rs9536234 0.51 0.9 1 hCV2983036 rs9527025 hCV30487772 rs9526998 0.51 0.9 1 hCV2983036 rs9527025 hCV30560346 rs9527021 0.51 0.9 1 hCV2983036 rs9527025 hCV32231920 rs12020187 0.51 0.9 1 hCV2983036 rs9527025 hDV72067820 rs9536282 0.51 0.9 0.9438 hCV2987250 rs301810 hCV11398434 rs1812457 0.51 0.515143538 0.7861 hCV2987250 rs301810 hCV11398437 rs1817367 0.51 0.515143538 0.7562 hCV2987250 rs301810 hCV11675962 rs10746481 0.51 0.515143538 0.7323 hCV2987250 rs301810 hCV1188731 rs4908514 0.51 0.515143538 0.6312 hCV2987250 rs301810 hCV15882429 rs2289732 0.51 0.515143538 0.6324 hCV2987250 rs301810 hCV27157507 rs6664000 0.51 0.515143538 0.6126 hCV2987250 rs301810 hCV2741759 rs11121179 0.51 0.515143538 0.5153 hCV2987250 rs301810 hCV27884601 rs4908776 0.51 0.515143538 0.5328 hCV2987250 rs301810 hCV27958354 rs4908762 0.51 0.515143538 0.8853 hCV2987250 rs301810 hCV29368919 rs4908513 0.51 0.515143538 0.5341 hCV2987250 rs301810 hCV2943451 rs902355 0.51 0.515143538 0.6527 hCV2987250 rs301810 hCV2943853 rs301793 0.51 0.515143538 0.5389 hCV2987250 rs301810 hCV2966436 rs11121174 0.51 0.515143538 0.5389 hCV2987250 rs301810 hCV2966437 rs11580417 0.51 0.515143538 0.6324 hCV2987250 rs301810 hCV2966441 rs6684863 0.51 0.515143538 0.6324 hCV2987250 rs301810 hCV2966444 rs11121171 0.51 0.515143538 0.6809 hCV2987250 rs301810 hCV29819064 rs6698079 0.51 0.515143538 0.7332 hCV2987250 rs301810 hCV29873524 rs7533113 0.51 0.515143538 0.6312 hCV2987250 rs301810 hCV29873526 rs6697997 0.51 0.515143538 0.8909 hCV2987250 rs301810 hCV29945430 rs7517436 0.51 0.515143538 0.6126 hCV2987250 rs301810 hCV30035535 rs7518204 0.51 0.515143538 0.5318 hCV2987250 rs301810 hCV30125699 rs4581300 0.51 0.515143538 0.7731 hCV2987250 rs301810 hCV30143725 rs6690050 0.51 0.515143538 0.7323 hCV2987250 rs301810 hCV30467730 rs6702457 0.51 0.515143538 0.633 hCV2987250 rs301810 hCV3086930 rs6658881 0.51 0.515143538 0.7185 hCV2987250 rs301810 hCV3086932 rs7533442 0.51 0.515143538 0.7185 hCV2987250 rs301810 hCV3086950 rs4908771 0.51 0.515143538 0.7323 hCV2987250 rs301810 hCV3086961 rs6703577 0.51 0.515143538 0.665 hCV2987250 rs301810 hCV3086971 rs6679948 0.51 0.515143538 0.6812 hCV2987250 rs301810 hCV3086972 rs6688329 0.51 0.515143538 0.7073 hCV2987250 rs301810 hCV3086998 rs7530863 0.51 0.515143538 0.8853 hCV2987250 rs301810 hCV3087000 rs1463055 0.51 0.515143538 0.7843 hCV2987250 rs301810 hCV3087003 rs6577500 0.51 0.515143538 0.7843 hCV2987250 rs301810 hCV3087015 rs11121198 0.51 0.515143538 0.8909 hCV2987250 rs301810 hCV3087016 rs2297867 0.51 0.515143538 0.7731 hCV2987250 rs301810 hCV32055284 rs12079653 0.51 0.515143538 0.6533 hCV2987250 rs301810 hCV32055470 rs6577506 0.51 0.515143538 0.7754 hCV2987250 rs301810 hCV32055474 rs10864359 0.51 0.515143538 0.665 hCV2987250 rs301810 hCV32055477 rs10779705 0.51 0.515143538 0.6812 hCV2987250 rs301810 hCV32055548 rs11121197 0.51 0.515143538 0.7843 hCV2987250 rs301810 hCV32055579 rs6577522 0.51 0.515143538 0.6308 hCV2987250 rs301810 hCV32055595 rs6577524 0.51 0.515143538 0.6312 hCV2987250 rs301810 hCV32055637 rs6577532 0.51 0.515143538 0.5618 hCV2987250 rs301810 hCV32055677 rs10864355 0.51 0.515143538 0.7843 hCV2987250 rs301810 hCV529178 rs301811 0.51 0.515143538 0.8909 hCV2987250 rs301810 hCV529182 rs301800 0.51 0.515143538 0.5618 hCV2987250 rs301810 hCV597227 rs301809 0.51 0.515143538 0.8909 hCV2987250 rs301810 hCV597229 rs301785 0.51 0.515143538 0.8909 hCV2987250 rs301810 hCV877241 rs301788 0.51 0.515143538 0.6134 hCV2987250 rs301810 hCV8823713 rs1472228 0.51 0.515143538 0.6126 hCV2987250 rs301810 hCV8824288 rs910582 0.51 0.515143538 0.7843 hCV2987250 rs301810 hCV8824394 rs1443929 0.51 0.515143538 0.5153 hCV2987250 rs301810 hCV8824424 rs1058790 0.51 0.515143538 0.5823 hCV2987250 rs301810 hCV8824425 rs1058791 0.51 0.515143538 0.5599 hCV2987250 rs301810 hCV8881145 rs1038008 0.51 0.515143538 0.6812 hCV2987250 rs301810 hCV8881146 rs1463054 0.51 0.515143538 0.7592 hCV2987250 rs301810 hCV8881157 rs1535158 0.51 0.515143538 0.6812 hCV2987250 rs301810 hCV8881161 rs926951 0.51 0.515143538 0.8853 hCV29873524 rs7533113 hCV1188731 rs4908514 0.51 0.906005924 1 hCV29873524 rs7533113 hCV1188735 rs10864366 0.51 0.906005924 1 hCV29873524 rs7533113 hCV27157507 rs6664000 0.51 0.906005924 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0.408966509 0.7435 hCV29952522 rs9457931 hCV27502709 rs3798158 0.51 0.408966509 0.7431 hCV29952522 rs9457931 hCV29109993 rs7757997 0.51 0.408966509 1 hCV29952522 rs9457931 hCV29109993 rs7757997 0.51 0.838470755 1 hCV29952522 rs9457931 hCV29683578 rs7761031 0.51 0.408966509 1 hCV29952522 rs9457931 hCV29683578 rs7761031 0.51 0.838470755 1 hCV29952522 rs9457931 hCV29774032 rs9457881 0.51 0.408966509 1 hCV29952522 rs9457931 hCV29774032 rs9457881 0.51 0.838470755 1 hCV29952522 rs9457931 hCV29809835 rs9457880 0.51 0.408966509 0.7436 hCV29952522 rs9457931 hCV30296556 rs10499313 0.51 0.408966509 0.7436 hCV29952522 rs9457931 hCV30350563 rs9457882 0.51 0.408966509 0.7436 hCV30136303 rs6914527 hCV11542275 rs3105258 0.51 0.9 0.9295 hCV30136303 rs6914527 hCV11542286 rs3125275 0.51 0.9 1 hCV30136303 rs6914527 hCV11559368 rs6899649 0.51 0.9 0.9428 hCV30136303 rs6914527 hCV11560148 rs11966562 0.51 0.9 0.9048 hCV30136303 rs6914527 hCV12026670 rs2047809 0.51 0.9 0.9244 hCV30136303 rs6914527 hCV238179 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hCV30233466 rs7513880 hCV29855298 rs6690928 0.51 0.771664644 1 hCV30233466 rs7513880 hCV29981708 rs7554486 0.51 0.771664644 0.7756 hCV30233466 rs7513880 hCV32055554 rs12024032 0.51 0.771664644 0.9066 hCV30233466 rs7513880 hCV32055587 rs10864367 0.51 0.771664644 1 hCV30233466 rs7513880 hCV32055630 rs4908518 0.51 0.771664644 0.8883 hCV30233466 rs7513880 hDV75072264 rs12403640 0.51 0.771664644 0.8888 hCV3026189 rs11739136 hCV15861099 rs2071161 0.51 0.9 1 hCV30264691 rs10508518 hCV29218874 rs7087976 0.51 0.9 1 hCV30264691 rs10508518 hCV29218875 rs7087834 0.51 0.9 1 hCV30264691 rs10508518 hCV3134992 rs4748342 0.51 0.9 1 hCV30264691 rs10508518 hCV3135019 rs7897550 0.51 0.9 0.9123 hCV30264691 rs10508518 hDV72006105 rs7916443 0.51 0.9 1 hCV30287627 rs6675443 hCV11398047 rs1922983 0.51 0.758102092 0.9094 hCV30287627 rs6675443 hCV11398445 rs1934138 0.51 0.758102092 1 hCV30287627 rs6675443 hCV11675339 rs7530745 0.51 0.758102092 0.9135 hCV30287627 rs6675443 hCV11675982 rs1953827 0.51 0.758102092 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hCV30454150 rs10516434 hCV30694936 rs6840610 0.51 0.9 0.9309 hCV30454150 rs10516434 hDV70961198 rs17498778 0.51 0.9 0.9309 hCV30454150 rs10516434 hDV70969482 rs17564872 0.51 0.9 0.9309 hCV30454150 rs10516434 hDV71951446 rs7689289 0.51 0.9 0.9309 hCV30467730 rs6702457 hCV11398434 rs1812457 0.51 0.534550731 0.9381 hCV30467730 rs6702457 hCV11398437 rs1817367 0.51 0.534550731 0.9276 hCV30467730 rs6702457 hCV11675962 rs10746481 0.51 0.534550731 1 hCV30467730 rs6702457 hCV1188664 rs2765511 0.51 0.534550731 0.54 hCV30467730 rs6702457 hCV1188665 rs2781060 0.51 0.534550731 0.556 hCV30467730 rs6702457 hCV1188731 rs4908514 0.51 0.534550731 0.8774 hCV30467730 rs6702457 hCV1188735 rs10864366 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV12040675 rs2038904 0.51 0.534550731 0.54 hCV30467730 rs6702457 hCV15882429 rs2289732 0.51 0.534550731 0.5549 hCV30467730 rs6702457 hCV15932991 rs2781067 0.51 0.534550731 0.5861 hCV30467730 rs6702457 hCV15932992 rs2781068 0.51 0.534550731 0.5389 hCV30467730 rs6702457 hCV27157507 rs6664000 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV27157524 rs6577531 0.51 0.534550731 0.8175 hCV30467730 rs6702457 hCV27884601 rs4908776 0.51 0.534550731 0.877 hCV30467730 rs6702457 hCV27958354 rs4908762 0.51 0.534550731 0.815 hCV30467730 rs6702457 hCV28023091 rs4908773 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV29368919 rs4908513 0.51 0.534550731 0.8774 hCV30467730 rs6702457 hCV2943451 rs902355 0.51 0.534550731 0.6259 hCV30467730 rs6702457 hCV2943853 rs301793 0.51 0.534550731 0.5549 hCV30467730 rs6702457 hCV2966436 rs11121174 0.51 0.534550731 0.5549 hCV30467730 rs6702457 hCV2966437 rs11580417 0.51 0.534550731 0.5549 hCV30467730 rs6702457 hCV2966441 rs6684863 0.51 0.534550731 0.5549 hCV30467730 rs6702457 hCV2966444 rs11121171 0.51 0.534550731 0.5975 hCV30467730 rs6702457 hCV29819064 rs6698079 0.51 0.534550731 0.919 hCV30467730 rs6702457 hCV2987250 rs301810 0.51 0.534550731 0.633 hCV30467730 rs6702457 hCV29873524 rs7533113 0.51 0.534550731 0.8774 hCV30467730 rs6702457 hCV29873526 rs6697997 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV29945430 rs7517436 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV30035535 rs7518204 0.51 0.534550731 0.877 hCV30467730 rs6702457 hCV30125699 rs4581300 0.51 0.534550731 0.815 hCV30467730 rs6702457 hCV30143725 rs6690050 0.51 0.534550731 0.8785 hCV30467730 rs6702457 hCV3086930 rs6658881 0.51 0.534550731 1 hCV30467730 rs6702457 hCV3086932 rs7533442 0.51 0.534550731 1 hCV30467730 rs6702457 hCV3086950 rs4908771 0.51 0.534550731 1 hCV30467730 rs6702457 hCV3086961 rs6703577 0.51 0.534550731 0.9345 hCV30467730 rs6702457 hCV3086971 rs6679948 0.51 0.534550731 0.9381 hCV30467730 rs6702457 hCV3086972 rs6688329 0.51 0.534550731 0.9345 hCV30467730 rs6702457 hCV3086998 rs7530863 0.51 0.534550731 0.815 hCV30467730 rs6702457 hCV3087000 rs1463055 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV3087003 rs6577500 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV3087015 rs11121198 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV3087016 rs2297867 0.51 0.534550731 0.815 hCV30467730 rs6702457 hCV32055284 rs12079653 0.51 0.534550731 0.6352 hCV30467730 rs6702457 hCV32055470 rs6577506 0.51 0.534550731 0.9345 hCV30467730 rs6702457 hCV32055474 rs10864359 0.51 0.534550731 0.9345 hCV30467730 rs6702457 hCV32055477 rs10779705 0.51 0.534550731 0.9381 hCV30467730 rs6702457 hCV32055527 rs10864364 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV32055548 rs11121197 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV32055579 rs6577522 0.51 0.534550731 0.8774 hCV30467730 rs6702457 hCV32055595 rs6577524 0.51 0.534550731 0.8774 hCV30467730 rs6702457 hCV32055596 rs6577525 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV32055625 rs6678590 0.51 0.534550731 0.7684 hCV30467730 rs6702457 hCV32055637 rs6577532 0.51 0.534550731 0.8069 hCV30467730 rs6702457 hCV32055662 rs6677249 0.51 0.534550731 0.6372 hCV30467730 rs6702457 hCV32055677 rs10864355 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV529178 rs301811 0.51 0.534550731 0.8246 hCV30467730 rs6702457 hCV529182 rs301800 0.51 0.534550731 0.5758 hCV30467730 rs6702457 hCV597227 rs301809 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV597229 rs301785 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV8823713 rs1472228 0.51 0.534550731 0.8704 hCV30467730 rs6702457 hCV8824248 rs1543711 0.51 0.534550731 0.54 hCV30467730 rs6702457 hCV8824288 rs910582 0.51 0.534550731 0.8248 hCV30467730 rs6702457 hCV8824424 rs1058790 0.51 0.534550731 0.5975 hCV30467730 rs6702457 hCV8824425 rs1058791 0.51 0.534550731 0.5737 hCV30467730 rs6702457 hCV8881145 rs1038008 0.51 0.534550731 0.9381 hCV30467730 rs6702457 hCV8881146 rs1463054 0.51 0.534550731 0.9064 hCV30467730 rs6702457 hCV8881157 rs1535158 0.51 0.534550731 0.9381 hCV30467730 rs6702457 hCV8881161 rs926951 0.51 0.534550731 0.815 hCV30534667 rs4996259 hCV26718978 rs7779312 0.51 0.9 0.9383 hCV30534667 rs4996259 hCV2677705 rs12670134 0.51 0.9 0.9021 hCV30534667 rs4996259 hCV2677722 rs1548868 0.51 0.9 1 hCV30534667 rs4996259 hCV2677723 rs3735442 0.51 0.9 1 hCV30534667 rs4996259 hCV29210278 rs7784056 0.51 0.9 1 hCV30586985 rs10126006 hCV11373123 rs1984003 0.51 0.485664418 0.6184 hCV30586985 rs10126006 hCV11765727 rs10781379 0.51 0.485664418 0.6121 hCV30586985 rs10126006 hCV11765729 rs7875659 0.51 0.485664418 0.6108 hCV30586985 rs10126006 hCV11765753 rs3793456 0.51 0.485664418 0.8904 hCV30586985 rs10126006 hCV1463101 rs7871596 0.51 0.485664418 0.6831 hCV30586985 rs10126006 hCV1463112 rs3763608 0.51 0.485664418 0.8497 hCV30586985 rs10126006 hCV1463185 rs953588 0.51 0.485664418 0.5648 hCV30586985 rs10126006 hCV1463216 rs4745581 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV1463218 rs1984004 0.51 0.485664418 0.6 hCV30586985 rs10126006 hCV1463222 rs4744808 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV1463225 rs4745577 0.51 0.485664418 0.6184 hCV30586985 rs10126006 hCV1463226 rs10890 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV1463232 rs9314854 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV1463235 rs2498430 0.51 0.485664418 0.6815 hCV30586985 rs10126006 hCV1463244 rs3793465 0.51 0.485664418 0.9422 hCV30586985 rs10126006 hCV1463247 rs3829064 0.51 0.485664418 0.6431 hCV30586985 rs10126006 hCV1463251 rs2498434 0.51 0.485664418 0.7097 hCV30586985 rs10126006 hCV1463252 rs3793461 0.51 0.485664418 0.9284 hCV30586985 rs10126006 hCV1463256 rs2309394 0.51 0.485664418 0.7296 hCV30586985 rs10126006 hCV15761059 rs2309393 0.51 0.485664418 0.9422 hCV30586985 rs10126006 hCV15892414 rs2498431 0.51 0.485664418 0.6815 hCV30586985 rs10126006 hCV15892430 rs2498433 0.51 0.485664418 0.5477 hCV30586985 rs10126006 hCV25609765 rs3829062 0.51 0.485664418 0.7296 hCV30586985 rs10126006 hCV26566199 rs3793467 0.51 0.485664418 0.9284 hCV30586985 rs10126006 hCV26566299 rs10869821 0.51 0.485664418 0.6497 hCV30586985 rs10126006 hCV27517372 rs3793457 0.51 0.485664418 0.67 hCV30586985 rs10126006 hCV28008078 rs4745543 0.51 0.485664418 0.8573 hCV30586985 rs10126006 hCV29861776 rs9411171 0.51 0.485664418 0.6431 hCV30586985 rs10126006 hCV31363797 rs11145043 0.51 0.485664418 0.9036 hCV30586985 rs10126006 hCV31363840 rs7875693 0.51 0.485664418 0.8834 hCV30586985 rs10126006 hCV31363841 rs7849347 0.51 0.485664418 0.8548 hCV30586985 rs10126006 hCV31363869 rs11145070 0.51 0.485664418 0.6279 hCV30586985 rs10126006 hCV31363888 rs7859021 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV31363984 rs7855905 0.51 0.485664418 0.8671 hCV30586985 rs10126006 hCV320569 rs9411170 0.51 0.485664418 0.6762 hCV30586985 rs10126006 hCV8785184 rs1411676 0.51 0.485664418 0.6184 hCV30586985 rs10126006 hCV8785185 rs1411675 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hCV9333267 rs1045632 0.51 0.485664418 0.6289 hCV30586985 rs10126006 hDV71871695 rs7047274 0.51 0.485664418 0.6902 hCV30606396 rs10438978 hCV15846640 rs2187375 0.51 0.9 0.9391 hCV30606396 rs10438978 hCV16140621 rs2156552 0.51 0.9 0.9392 hCV30606396 rs10438978 hCV27889421 rs4939883 0.51 0.9 1 hCV30606396 rs10438978 hCV29202191 rs7240405 0.51 0.9 0.9694 hCV30606396 rs10438978 hCV29202193 rs7239867 0.51 0.9 0.9694 hCV30606396 rs10438978 hCV29202195 rs8086351 0.51 0.9 0.9438 hCV30606396 rs10438978 hCV30011938 rs7241918 0.51 0.9 1 hCV30606396 rs10438978 hDV71197604 rs1943981 0.51 0.9 0.9459 hCV30764105 rs12521915 hCV15758655 rs2303122 0.51 0.9 1 hCV30764105 rs12521915 hCV2929716 rs7725246 0.51 0.9 0.9371 hCV3086932 rs7533442 hCV11398434 rs1812457 0.51 0.411159327 0.9345 hCV3086932 rs7533442 hCV11398437 rs1817367 0.51 0.411159327 0.8687 hCV3086932 rs7533442 hCV11675962 rs10746481 0.51 0.411159327 1 hCV3086932 rs7533442 hCV1188659 rs3820037 0.51 0.411159327 0.4725 hCV3086932 rs7533442 hCV1188660 rs6660137 0.51 0.411159327 0.4816 hCV3086932 rs7533442 hCV1188664 rs2765511 0.51 0.411159327 0.5167 hCV3086932 rs7533442 hCV1188665 rs2781060 0.51 0.411159327 0.5328 hCV3086932 rs7533442 hCV1188676 rs11121247 0.51 0.411159327 0.4816 hCV3086932 rs7533442 hCV1188731 rs4908514 0.51 0.411159327 0.8704 hCV3086932 rs7533442 hCV1188735 rs10864366 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV12040675 rs2038904 0.51 0.411159327 0.5167 hCV3086932 rs7533442 hCV15882429 rs2289732 0.51 0.411159327 0.5302 hCV3086932 rs7533442 hCV15932991 rs2781067 0.51 0.411159327 0.5621 hCV3086932 rs7533442 hCV15932992 rs2781068 0.51 0.411159327 0.5153 hCV3086932 rs7533442 hCV27157507 rs6664000 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV27157524 rs6577531 0.51 0.411159327 0.8069 hCV3086932 rs7533442 hCV2741759 rs11121179 0.51 0.411159327 0.5418 hCV3086932 rs7533442 hCV27474399 rs3753275 0.51 0.411159327 0.4658 hCV3086932 rs7533442 hCV27884601 rs4908776 0.51 0.411159327 0.87 hCV3086932 rs7533442 hCV27958354 rs4908762 0.51 0.411159327 0.8501 hCV3086932 rs7533442 hCV28023091 rs4908773 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV29368919 rs4908513 0.51 0.411159327 0.8704 hCV3086932 rs7533442 hCV2943451 rs902355 0.51 0.411159327 0.6039 hCV3086932 rs7533442 hCV2943853 rs301793 0.51 0.411159327 0.5302 hCV3086932 rs7533442 hCV2966436 rs11121174 0.51 0.411159327 0.5302 hCV3086932 rs7533442 hCV2966437 rs11580417 0.51 0.411159327 0.5302 hCV3086932 rs7533442 hCV2966441 rs6684863 0.51 0.411159327 0.5302 hCV3086932 rs7533442 hCV2966444 rs11121171 0.51 0.411159327 0.5747 hCV3086932 rs7533442 hCV29819064 rs6698079 0.51 0.411159327 0.9184 hCV3086932 rs7533442 hCV2987250 rs301810 0.51 0.411159327 0.7185 hCV3086932 rs7533442 hCV29873524 rs7533113 0.51 0.411159327 0.8704 hCV3086932 rs7533442 hCV29873526 rs6697997 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV29945430 rs7517436 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV30035535 rs7518204 0.51 0.411159327 0.87 hCV3086932 rs7533442 hCV30125699 rs4581300 0.51 0.411159327 0.7911 hCV3086932 rs7533442 hCV30143725 rs6690050 0.51 0.411159327 0.8714 hCV3086932 rs7533442 hCV30287627 rs6675443 0.51 0.411159327 0.4429 hCV3086932 rs7533442 hCV30341660 rs6681362 0.51 0.411159327 0.4193 hCV3086932 rs7533442 hCV30467730 rs6702457 0.51 0.411159327 1 hCV3086932 rs7533442 hCV3086930 rs6658881 0.51 0.411159327 1 hCV3086932 rs7533442 hCV3086941 rs7556169 0.51 0.411159327 0.4162 hCV3086932 rs7533442 hCV3086950 rs4908771 0.51 0.411159327 1 hCV3086932 rs7533442 hCV3086952 rs6577514 0.51 0.411159327 0.464 hCV3086932 rs7533442 hCV3086961 rs6703577 0.51 0.411159327 0.9091 hCV3086932 rs7533442 hCV3086971 rs6679948 0.51 0.411159327 0.9345 hCV3086932 rs7533442 hCV3086972 rs6688329 0.51 0.411159327 0.9305 hCV3086932 rs7533442 hCV3086978 rs7526171 0.51 0.411159327 0.439 hCV3086932 rs7533442 hCV3086998 rs7530863 0.51 0.411159327 0.8501 hCV3086932 rs7533442 hCV3087000 rs1463055 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV3087003 rs6577500 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV3087015 rs11121198 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV3087016 rs2297867 0.51 0.411159327 0.8228 hCV3086932 rs7533442 hCV32055284 rs12079653 0.51 0.411159327 0.6146 hCV3086932 rs7533442 hCV32055470 rs6577506 0.51 0.411159327 0.9091 hCV3086932 rs7533442 hCV32055474 rs10864359 0.51 0.411159327 0.85 hCV3086932 rs7533442 hCV32055477 rs10779705 0.51 0.411159327 0.9345 hCV3086932 rs7533442 hCV32055496 rs11121215 0.51 0.411159327 0.4393 hCV3086932 rs7533442 hCV32055527 rs10864364 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV32055548 rs11121197 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV32055579 rs6577522 0.51 0.411159327 0.8704 hCV3086932 rs7533442 hCV32055595 rs6577524 0.51 0.411159327 0.8704 hCV3086932 rs7533442 hCV32055596 rs6577525 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV32055625 rs6678590 0.51 0.411159327 0.7419 hCV3086932 rs7533442 hCV32055637 rs6577532 0.51 0.411159327 0.6768 hCV3086932 rs7533442 hCV32055662 rs6677249 0.51 0.411159327 0.5186 hCV3086932 rs7533442 hCV32055677 rs10864355 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV529178 rs301811 0.51 0.411159327 0.8149 hCV3086932 rs7533442 hCV529182 rs301800 0.51 0.411159327 0.5676 hCV3086932 rs7533442 hCV597227 rs301809 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV597229 rs301785 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV877241 rs301788 0.51 0.411159327 0.5418 hCV3086932 rs7533442 hCV8823713 rs1472228 0.51 0.411159327 0.8213 hCV3086932 rs7533442 hCV8824244 rs1006950 0.51 0.411159327 0.4725 hCV3086932 rs7533442 hCV8824248 rs1543711 0.51 0.411159327 0.5167 hCV3086932 rs7533442 hCV8824288 rs910582 0.51 0.411159327 0.815 hCV3086932 rs7533442 hCV8824394 rs1443929 0.51 0.411159327 0.5418 hCV3086932 rs7533442 hCV8824424 rs1058790 0.51 0.411159327 0.5747 hCV3086932 rs7533442 hCV8824425 rs1058791 0.51 0.411159327 0.5144 hCV3086932 rs7533442 hCV8881145 rs1038008 0.51 0.411159327 0.9345 hCV3086932 rs7533442 hCV8881146 rs1463054 0.51 0.411159327 0.9059 hCV3086932 rs7533442 hCV8881157 rs1535158 0.51 0.411159327 0.9345 hCV3086932 rs7533442 hCV8881161 rs926951 0.51 0.411159327 0.8501 hCV3086932 rs7533442 hDV77058075 rs4908506 0.51 0.411159327 0.4162 hCV3086950 rs4908771 hCV11398434 rs1812457 0.51 0.532308891 0.9381 hCV3086950 rs4908771 hCV11398437 rs1817367 0.51 0.532308891 0.9276 hCV3086950 rs4908771 hCV11675962 rs10746481 0.51 0.532308891 1 hCV3086950 rs4908771 hCV1188664 rs2765511 0.51 0.532308891 0.54 hCV3086950 rs4908771 hCV1188665 rs2781060 0.51 0.532308891 0.556 hCV3086950 rs4908771 hCV1188731 rs4908514 0.51 0.532308891 0.8774 hCV3086950 rs4908771 hCV1188735 rs10864366 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV12040675 rs2038904 0.51 0.532308891 0.54 hCV3086950 rs4908771 hCV15882429 rs2289732 0.51 0.532308891 0.5549 hCV3086950 rs4908771 hCV15932991 rs2781067 0.51 0.532308891 0.5861 hCV3086950 rs4908771 hCV15932992 rs2781068 0.51 0.532308891 0.5389 hCV3086950 rs4908771 hCV27157507 rs6664000 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV27157524 rs6577531 0.51 0.532308891 0.8175 hCV3086950 rs4908771 hCV27884601 rs4908776 0.51 0.532308891 0.877 hCV3086950 rs4908771 hCV27958354 rs4908762 0.51 0.532308891 0.815 hCV3086950 rs4908771 hCV28023091 rs4908773 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV29368919 rs4908513 0.51 0.532308891 0.8774 hCV3086950 rs4908771 hCV2943451 rs902355 0.51 0.532308891 0.6259 hCV3086950 rs4908771 hCV2943853 rs301793 0.51 0.532308891 0.5549 hCV3086950 rs4908771 hCV2966436 rs11121174 0.51 0.532308891 0.5549 hCV3086950 rs4908771 hCV2966437 rs11580417 0.51 0.532308891 0.5549 hCV3086950 rs4908771 hCV2966441 rs6684863 0.51 0.532308891 0.5549 hCV3086950 rs4908771 hCV2966444 rs11121171 0.51 0.532308891 0.5975 hCV3086950 rs4908771 hCV29819064 rs6698079 0.51 0.532308891 0.919 hCV3086950 rs4908771 hCV2987250 rs301810 0.51 0.532308891 0.7323 hCV3086950 rs4908771 hCV29873524 rs7533113 0.51 0.532308891 0.8774 hCV3086950 rs4908771 hCV29873526 rs6697997 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV29945430 rs7517436 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV30035535 rs7518204 0.51 0.532308891 0.877 hCV3086950 rs4908771 hCV30125699 rs4581300 0.51 0.532308891 0.815 hCV3086950 rs4908771 hCV30143725 rs6690050 0.51 0.532308891 0.8785 hCV3086950 rs4908771 hCV30467730 rs6702457 0.51 0.532308891 1 hCV3086950 rs4908771 hCV3086930 rs6658881 0.51 0.532308891 1 hCV3086950 rs4908771 hCV3086932 rs7533442 0.51 0.532308891 1 hCV3086950 rs4908771 hCV3086961 rs6703577 0.51 0.532308891 0.9345 hCV3086950 rs4908771 hCV3086971 rs6679948 0.51 0.532308891 0.9381 hCV3086950 rs4908771 hCV3086972 rs6688329 0.51 0.532308891 0.9345 hCV3086950 rs4908771 hCV3086998 rs7530863 0.51 0.532308891 0.815 hCV3086950 rs4908771 hCV3087000 rs1463055 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV3087003 rs6577500 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV3087015 rs11121198 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV3087016 rs2297867 0.51 0.532308891 0.815 hCV3086950 rs4908771 hCV32055284 rs12079653 0.51 0.532308891 0.6352 hCV3086950 rs4908771 hCV32055470 rs6577506 0.51 0.532308891 0.9345 hCV3086950 rs4908771 hCV32055474 rs10864359 0.51 0.532308891 0.9345 hCV3086950 rs4908771 hCV32055477 rs10779705 0.51 0.532308891 0.9381 hCV3086950 rs4908771 hCV32055527 rs10864364 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV32055548 rs11121197 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV32055579 rs6577522 0.51 0.532308891 0.8774 hCV3086950 rs4908771 hCV32055595 rs6577524 0.51 0.532308891 0.8774 hCV3086950 rs4908771 hCV32055596 rs6577525 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV32055625 rs6678590 0.51 0.532308891 0.7684 hCV3086950 rs4908771 hCV32055637 rs6577532 0.51 0.532308891 0.8069 hCV3086950 rs4908771 hCV32055662 rs6677249 0.51 0.532308891 0.6372 hCV3086950 rs4908771 hCV32055677 rs10864355 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV529178 rs301811 0.51 0.532308891 0.8246 hCV3086950 rs4908771 hCV529182 rs301800 0.51 0.532308891 0.5758 hCV3086950 rs4908771 hCV597227 rs301809 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV597229 rs301785 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV8823713 rs1472228 0.51 0.532308891 0.8704 hCV3086950 rs4908771 hCV8824248 rs1543711 0.51 0.532308891 0.54 hCV3086950 rs4908771 hCV8824288 rs910582 0.51 0.532308891 0.8248 hCV3086950 rs4908771 hCV8824424 rs1058790 0.51 0.532308891 0.5975 hCV3086950 rs4908771 hCV8824425 rs1058791 0.51 0.532308891 0.5737 hCV3086950 rs4908771 hCV8881145 rs1038008 0.51 0.532308891 0.9381 hCV3086950 rs4908771 hCV8881146 rs1463054 0.51 0.532308891 0.9064 hCV3086950 rs4908771 hCV8881157 rs1535158 0.51 0.532308891 0.9381 hCV3086950 rs4908771 hCV8881161 rs926951 0.51 0.532308891 0.815 hCV3086961 rs6703577 hCV11398434 rs1812457 0.51 0.900934013 1 hCV3086961 rs6703577 hCV11398437 rs1817367 0.51 0.900934013 0.9642 hCV3086961 rs6703577 hCV11675962 rs10746481 0.51 0.900934013 0.9345 hCV3086961 rs6703577 hCV27958354 rs4908762 0.51 0.900934013 0.9379 hCV3086961 rs6703577 hCV29819064 rs6698079 0.51 0.900934013 1 hCV3086961 rs6703577 hCV30143725 rs6690050 0.51 0.900934013 0.9345 hCV3086961 rs6703577 hCV30467730 rs6702457 0.51 0.900934013 0.9345 hCV3086961 rs6703577 hCV3086930 rs6658881 0.51 0.900934013 0.9091 hCV3086961 rs6703577 hCV3086932 rs7533442 0.51 0.900934013 0.9091 hCV3086961 rs6703577 hCV3086950 rs4908771 0.51 0.900934013 0.9345 hCV3086961 rs6703577 hCV3086971 rs6679948 0.51 0.900934013 1 hCV3086961 rs6703577 hCV3086972 rs6688329 0.51 0.900934013 1 hCV3086961 rs6703577 hCV3086998 rs7530863 0.51 0.900934013 0.9379 hCV3086961 rs6703577 hCV3087016 rs2297867 0.51 0.900934013 0.9091 hCV3086961 rs6703577 hCV32055470 rs6577506 0.51 0.900934013 1 hCV3086961 rs6703577 hCV32055474 rs10864359 0.51 0.900934013 0.9379 hCV3086961 rs6703577 hCV32055477 rs10779705 0.51 0.900934013 1 hCV3086961 rs6703577 hCV8881145 rs1038008 0.51 0.900934013 1 hCV3086961 rs6703577 hCV8881146 rs1463054 0.51 0.900934013 1 hCV3086961 rs6703577 hCV8881157 rs1535158 0.51 0.900934013 1 hCV3086961 rs6703577 hCV8881161 rs926951 0.51 0.900934013 0.9379 hCV3087000 rs1463055 hCV11398434 rs1812457 0.51 0.532906869 0.8824 hCV3087000 rs1463055 hCV11398437 rs1817367 0.51 0.532906869 0.8638 hCV3087000 rs1463055 hCV11675962 rs10746481 0.51 0.532906869 0.8248 hCV3087000 rs1463055 hCV1188731 rs4908514 0.51 0.532906869 0.7112 hCV3087000 rs1463055 hCV1188735 rs10864366 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV15882429 rs2289732 0.51 0.532906869 0.7153 hCV3087000 rs1463055 hCV25996298 rs7535752 0.51 0.532906869 0.5809 hCV3087000 rs1463055 hCV27157507 rs6664000 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV27157524 rs6577531 0.51 0.532906869 0.6596 hCV3087000 rs1463055 hCV2741759 rs11121179 0.51 0.532906869 0.6996 hCV3087000 rs1463055 hCV27474399 rs3753275 0.51 0.532906869 0.5827 hCV3087000 rs1463055 hCV27884601 rs4908776 0.51 0.532906869 0.7103 hCV3087000 rs1463055 hCV27958354 rs4908762 0.51 0.532906869 1 hCV3087000 rs1463055 hCV28023091 rs4908773 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV29368919 rs4908513 0.51 0.532906869 0.7112 hCV3087000 rs1463055 hCV2943451 rs902355 0.51 0.532906869 0.7442 hCV3087000 rs1463055 hCV2943853 rs301793 0.51 0.532906869 0.7153 hCV3087000 rs1463055 hCV2966436 rs11121174 0.51 0.532906869 0.7153 hCV3087000 rs1463055 hCV2966437 rs11580417 0.51 0.532906869 0.7153 hCV3087000 rs1463055 hCV2966441 rs6684863 0.51 0.532906869 0.7153 hCV3087000 rs1463055 hCV2966444 rs11121171 0.51 0.532906869 0.7672 hCV3087000 rs1463055 hCV29819064 rs6698079 0.51 0.532906869 0.8488 hCV3087000 rs1463055 hCV2987250 rs301810 0.51 0.532906869 0.7843 hCV3087000 rs1463055 hCV29873524 rs7533113 0.51 0.532906869 0.7112 hCV3087000 rs1463055 hCV29873526 rs6697997 0.51 0.532906869 1 hCV3087000 rs1463055 hCV29945430 rs7517436 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV30035535 rs7518204 0.51 0.532906869 0.7101 hCV3087000 rs1463055 hCV30125699 rs4581300 0.51 0.532906869 1 hCV3087000 rs1463055 hCV30143725 rs6690050 0.51 0.532906869 0.8248 hCV3087000 rs1463055 hCV30467730 rs6702457 0.51 0.532906869 0.8248 hCV3087000 rs1463055 hCV3086930 rs6658881 0.51 0.532906869 0.815 hCV3087000 rs1463055 hCV3086932 rs7533442 0.51 0.532906869 0.815 hCV3087000 rs1463055 hCV3086950 rs4908771 0.51 0.532906869 0.8248 hCV3087000 rs1463055 hCV3086961 rs6703577 0.51 0.532906869 0.8759 hCV3087000 rs1463055 hCV3086971 rs6679948 0.51 0.532906869 0.8824 hCV3087000 rs1463055 hCV3086972 rs6688329 0.51 0.532906869 0.8759 hCV3087000 rs1463055 hCV3086998 rs7530863 0.51 0.532906869 1 hCV3087000 rs1463055 hCV3087003 rs6577500 0.51 0.532906869 1 hCV3087000 rs1463055 hCV3087015 rs11121198 0.51 0.532906869 1 hCV3087000 rs1463055 hCV3087016 rs2297867 0.51 0.532906869 1 hCV3087000 rs1463055 hCV32055284 rs12079653 0.51 0.532906869 0.6985 hCV3087000 rs1463055 hCV32055470 rs6577506 0.51 0.532906869 0.8759 hCV3087000 rs1463055 hCV32055474 rs10864359 0.51 0.532906869 0.8759 hCV3087000 rs1463055 hCV32055477 rs10779705 0.51 0.532906869 0.8824 hCV3087000 rs1463055 hCV32055527 rs10864364 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV32055548 rs11121197 0.51 0.532906869 1 hCV3087000 rs1463055 hCV32055579 rs6577522 0.51 0.532906869 0.7109 hCV3087000 rs1463055 hCV32055595 rs6577524 0.51 0.532906869 0.7112 hCV3087000 rs1463055 hCV32055596 rs6577525 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV32055625 rs6678590 0.51 0.532906869 0.6074 hCV3087000 rs1463055 hCV32055637 rs6577532 0.51 0.532906869 0.6408 hCV3087000 rs1463055 hCV32055677 rs10864355 0.51 0.532906869 1 hCV3087000 rs1463055 hCV529178 rs301811 0.51 0.532906869 1 hCV3087000 rs1463055 hCV529182 rs301800 0.51 0.532906869 0.7545 hCV3087000 rs1463055 hCV597227 rs301809 0.51 0.532906869 1 hCV3087000 rs1463055 hCV597229 rs301785 0.51 0.532906869 1 hCV3087000 rs1463055 hCV877241 rs301788 0.51 0.532906869 0.6996 hCV3087000 rs1463055 hCV8823713 rs1472228 0.51 0.532906869 0.6952 hCV3087000 rs1463055 hCV8824288 rs910582 0.51 0.532906869 1 hCV3087000 rs1463055 hCV8824394 rs1443929 0.51 0.532906869 0.6996 hCV3087000 rs1463055 hCV8824424 rs1058790 0.51 0.532906869 0.7672 hCV3087000 rs1463055 hCV8824425 rs1058791 0.51 0.532906869 0.754 hCV3087000 rs1463055 hCV8881145 rs1038008 0.51 0.532906869 0.8824 hCV3087000 rs1463055 hCV8881146 rs1463054 0.51 0.532906869 0.8271 hCV3087000 rs1463055 hCV8881157 rs1535158 0.51 0.532906869 0.8824 hCV3087000 rs1463055 hCV8881161 rs926951 0.51 0.532906869 1 hCV3087003 rs6577500 hCV27958354 rs4908762 0.51 0.967969018 1 hCV3087003 rs6577500 hCV29873526 rs6697997 0.51 0.967969018 1 hCV3087003 rs6577500 hCV30125699 rs4581300 0.51 0.967969018 1 hCV3087003 rs6577500 hCV3086998 rs7530863 0.51 0.967969018 1 hCV3087003 rs6577500 hCV3087000 rs1463055 0.51 0.967969018 1 hCV3087003 rs6577500 hCV3087015 rs11121198 0.51 0.967969018 1 hCV3087003 rs6577500 hCV3087016 rs2297867 0.51 0.967969018 1 hCV3087003 rs6577500 hCV32055548 rs11121197 0.51 0.967969018 1 hCV3087003 rs6577500 hCV32055677 rs10864355 0.51 0.967969018 1 hCV3087003 rs6577500 hCV529178 rs301811 0.51 0.967969018 1 hCV3087003 rs6577500 hCV597227 rs301809 0.51 0.967969018 1 hCV3087003 rs6577500 hCV597229 rs301785 0.51 0.967969018 1 hCV3087003 rs6577500 hCV8824288 rs910582 0.51 0.967969018 1 hCV3087003 rs6577500 hCV8881161 rs926951 0.51 0.967969018 1 hCV3087008 rs12136689 hCV11675387 rs2120461 0.51 0.694720473 0.7177 hCV3087008 rs12136689 hCV1265821 rs6577489 0.51 0.694720473 0.9622 hCV3087008 rs12136689 hCV1265845 rs4908501 0.51 0.694720473 0.9607 hCV3087008 rs12136689 hCV1417732 rs12128827 0.51 0.694720473 0.8134 hCV3087008 rs12136689 hCV2943852 rs301795 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2958030 rs3765971 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2958031 rs2252865 0.51 0.694720473 0.7735 hCV3087008 rs12136689 hCV2966430 rs2708633 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2966432 rs6678140 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2966435 rs894875 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2987217 rs301791 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2987218 rs301790 0.51 0.694720473 0.7225 hCV3087008 rs12136689 hCV2987219 rs301789 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2987237 rs172531 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV2987238 rs301801 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV3086955 rs4908769 0.51 0.694720473 0.9612 hCV3087008 rs12136689 hCV32055281 rs10779702 0.51 0.694720473 0.7735 hCV3087008 rs12136689 hCV32055303 rs2784736 0.51 0.694720473 0.7018 hCV3087008 rs12136689 hCV32055534 rs12125525 0.51 0.694720473 0.8589 hCV3087008 rs12136689 hCV32055581 rs12123076 0.51 0.694720473 0.7789 hCV3087008 rs12136689 hCV32055778 rs6577497 0.51 0.694720473 0.8349 hCV3087008 rs12136689 hCV8823613 rs953043 0.51 0.694720473 0.8852 hCV3087008 rs12136689 hCV8824315 rs302719 0.51 0.694720473 0.7018 hCV3087015 rs11121198 hCV11398434 rs1812457 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV11398437 rs1817367 0.51 0.534576608 0.8638 hCV3087015 rs11121198 hCV11675962 rs10746481 0.51 0.534576608 0.8248 hCV3087015 rs11121198 hCV1188731 rs4908514 0.51 0.534576608 0.7112 hCV3087015 rs11121198 hCV1188735 rs10864366 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV15882429 rs2289732 0.51 0.534576608 0.7153 hCV3087015 rs11121198 hCV25996298 rs7535752 0.51 0.534576608 0.5809 hCV3087015 rs11121198 hCV27157507 rs6664000 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV27157524 rs6577531 0.51 0.534576608 0.6596 hCV3087015 rs11121198 hCV2741759 rs11121179 0.51 0.534576608 0.6996 hCV3087015 rs11121198 hCV27474399 rs3753275 0.51 0.534576608 0.5827 hCV3087015 rs11121198 hCV27884601 rs4908776 0.51 0.534576608 0.7103 hCV3087015 rs11121198 hCV27958354 rs4908762 0.51 0.534576608 1 hCV3087015 rs11121198 hCV28023091 rs4908773 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV29368919 rs4908513 0.51 0.534576608 0.7112 hCV3087015 rs11121198 hCV2943451 rs902355 0.51 0.534576608 0.7442 hCV3087015 rs11121198 hCV2943853 rs301793 0.51 0.534576608 0.7153 hCV3087015 rs11121198 hCV2966436 rs11121174 0.51 0.534576608 0.7153 hCV3087015 rs11121198 hCV2966437 rs11580417 0.51 0.534576608 0.7153 hCV3087015 rs11121198 hCV2966441 rs6684863 0.51 0.534576608 0.7153 hCV3087015 rs11121198 hCV2966444 rs11121171 0.51 0.534576608 0.7672 hCV3087015 rs11121198 hCV29819064 rs6698079 0.51 0.534576608 0.8488 hCV3087015 rs11121198 hCV2987250 rs301810 0.51 0.534576608 0.8909 hCV3087015 rs11121198 hCV29873524 rs7533113 0.51 0.534576608 0.7112 hCV3087015 rs11121198 hCV29873526 rs6697997 0.51 0.534576608 1 hCV3087015 rs11121198 hCV29945430 rs7517436 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV30035535 rs7518204 0.51 0.534576608 0.7101 hCV3087015 rs11121198 hCV30125699 rs4581300 0.51 0.534576608 1 hCV3087015 rs11121198 hCV30143725 rs6690050 0.51 0.534576608 0.8248 hCV3087015 rs11121198 hCV30467730 rs6702457 0.51 0.534576608 0.8248 hCV3087015 rs11121198 hCV3086930 rs6658881 0.51 0.534576608 0.815 hCV3087015 rs11121198 hCV3086932 rs7533442 0.51 0.534576608 0.815 hCV3087015 rs11121198 hCV3086950 rs4908771 0.51 0.534576608 0.8248 hCV3087015 rs11121198 hCV3086961 rs6703577 0.51 0.534576608 0.8759 hCV3087015 rs11121198 hCV3086971 rs6679948 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV3086972 rs6688329 0.51 0.534576608 0.8759 hCV3087015 rs11121198 hCV3086998 rs7530863 0.51 0.534576608 1 hCV3087015 rs11121198 hCV3087000 rs1463055 0.51 0.534576608 1 hCV3087015 rs11121198 hCV3087003 rs6577500 0.51 0.534576608 1 hCV3087015 rs11121198 hCV3087016 rs2297867 0.51 0.534576608 1 hCV3087015 rs11121198 hCV32055284 rs12079653 0.51 0.534576608 0.6985 hCV3087015 rs11121198 hCV32055470 rs6577506 0.51 0.534576608 0.8759 hCV3087015 rs11121198 hCV32055474 rs10864359 0.51 0.534576608 0.8759 hCV3087015 rs11121198 hCV32055477 rs10779705 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV32055527 rs10864364 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV32055548 rs11121197 0.51 0.534576608 1 hCV3087015 rs11121198 hCV32055579 rs6577522 0.51 0.534576608 0.7109 hCV3087015 rs11121198 hCV32055595 rs6577524 0.51 0.534576608 0.7112 hCV3087015 rs11121198 hCV32055596 rs6577525 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV32055625 rs6678590 0.51 0.534576608 0.6074 hCV3087015 rs11121198 hCV32055637 rs6577532 0.51 0.534576608 0.6408 hCV3087015 rs11121198 hCV32055677 rs10864355 0.51 0.534576608 1 hCV3087015 rs11121198 hCV529178 rs301811 0.51 0.534576608 1 hCV3087015 rs11121198 hCV529182 rs301800 0.51 0.534576608 0.7545 hCV3087015 rs11121198 hCV597227 rs301809 0.51 0.534576608 1 hCV3087015 rs11121198 hCV597229 rs301785 0.51 0.534576608 1 hCV3087015 rs11121198 hCV877241 rs301788 0.51 0.534576608 0.6996 hCV3087015 rs11121198 hCV8823713 rs1472228 0.51 0.534576608 0.6952 hCV3087015 rs11121198 hCV8824288 rs910582 0.51 0.534576608 1 hCV3087015 rs11121198 hCV8824394 rs1443929 0.51 0.534576608 0.6996 hCV3087015 rs11121198 hCV8824424 rs1058790 0.51 0.534576608 0.7672 hCV3087015 rs11121198 hCV8824425 rs1058791 0.51 0.534576608 0.754 hCV3087015 rs11121198 hCV8881145 rs1038008 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV8881146 rs1463054 0.51 0.534576608 0.8271 hCV3087015 rs11121198 hCV8881157 rs1535158 0.51 0.534576608 0.8824 hCV3087015 rs11121198 hCV8881161 rs926951 0.51 0.534576608 1 hCV3087016 rs2297867 hCV27958354 rs4908762 0.51 0.936425384 0.9694 hCV3087016 rs2297867 hCV29873526 rs6697997 0.51 0.936425384 1 hCV3087016 rs2297867 hCV3086998 rs7530863 0.51 0.936425384 0.9694 hCV3087016 rs2297867 hCV3087000 rs1463055 0.51 0.936425384 1 hCV3087016 rs2297867 hCV3087003 rs6577500 0.51 0.936425384 1 hCV3087016 rs2297867 hCV3087015 rs11121198 0.51 0.936425384 1 hCV3087016 rs2297867 hCV32055548 rs11121197 0.51 0.936425384 1 hCV3087016 rs2297867 hCV32055677 rs10864355 0.51 0.936425384 1 hCV3087016 rs2297867 hCV529178 rs301811 0.51 0.936425384 1 hCV3087016 rs2297867 hCV597227 rs301809 0.51 0.936425384 1 hCV3087016 rs2297867 hCV597229 rs301785 0.51 0.936425384 1 hCV3087016 rs2297867 hCV8824288 rs910582 0.51 0.936425384 1 hCV3087016 rs2297867 hCV8881161 rs926951 0.51 0.936425384 0.9694 hCV31145250 rs10889353 hCV11864156 rs10889334 0.51 0.9 1 hCV31145250 rs10889353 hCV11864162 rs1167998 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV11865171 rs11208004 0.51 0.9 1 hCV31145250 rs10889353 hCV11865185 rs10789117 0.51 0.9 0.979 hCV31145250 rs10889353 hCV11865201 rs10159255 0.51 0.9 0.979 hCV31145250 rs10889353 hCV12103105 rs1184865 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV12103127 rs1979722 0.51 0.9 0.9789 hCV31145250 rs10889353 hCV12103499 rs2029763 0.51 0.9 1 hCV31145250 rs10889353 hCV12103502 rs1168023 0.51 0.9 0.958 hCV31145250 rs10889353 hCV1236535 rs1168042 0.51 0.9 0.959 hCV31145250 rs10889353 hCV149783 rs1168045 0.51 0.9 0.979 hCV31145250 rs10889353 hCV16214290 rs2366638 0.51 0.9 0.959 hCV31145250 rs10889353 hCV1778957 rs3913007 0.51 0.9 1 hCV31145250 rs10889353 hCV1778958 rs634341 0.51 0.9 0.9558 hCV31145250 rs10889353 hCV1778963 rs10158897 0.51 0.9 0.979 hCV31145250 rs10889353 hCV1778964 rs659656 0.51 0.9 1 hCV31145250 rs10889353 hCV1778965 rs637723 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV1918028 rs10157265 0.51 0.9 0.958 hCV31145250 rs10889353 hCV1918041 rs4587594 0.51 0.9 1 hCV31145250 rs10889353 hCV1918054 rs10889347 0.51 0.9 0.979 hCV31145250 rs10889353 hCV2015148 rs11208007 0.51 0.9 0.9032 hCV31145250 rs10889353 hCV25971202 rs10889335 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV26412183 rs1748199 0.51 0.9 0.9577 hCV31145250 rs10889353 hCV26412184 rs11207990 0.51 0.9 0.9521 hCV31145250 rs10889353 hCV27320451 rs4350231 0.51 0.9 0.979 hCV31145250 rs10889353 hCV27320465 rs641540 0.51 0.9 0.9586 hCV31145250 rs10889353 hCV29103721 rs6678483 0.51 0.9 0.979 hCV31145250 rs10889353 hCV29103722 rs6675401 0.51 0.9 0.979 hCV31145250 rs10889353 hCV29103723 rs4329540 0.51 0.9 0.979 hCV31145250 rs10889353 hCV29647381 rs6690733 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV29749081 rs10493322 0.51 0.9 1 hCV31145250 rs10889353 hCV30224093 rs7539035 0.51 0.9 0.979 hCV31145250 rs10889353 hCV31145255 rs11208000 0.51 0.9 0.9551 hCV31145250 rs10889353 hCV31145262 rs10889352 0.51 0.9 1 hCV31145250 rs10889353 hCV31145264 rs10789119 0.51 0.9 1 hCV31145250 rs10889353 hCV31145266 rs10789118 0.51 0.9 1 hCV31145250 rs10889353 hCV31145267 rs11485618 0.51 0.9 1 hCV31145250 rs10889353 hCV31145269 rs6587980 0.51 0.9 0.979 hCV31145250 rs10889353 hCV31145277 rs10889350 0.51 0.9 0.959 hCV31145250 rs10889353 hCV31145279 rs10889349 0.51 0.9 0.959 hCV31145250 rs10889353 hCV31145282 rs11207997 0.51 0.9 0.9169 hCV31145250 rs10889353 hCV31145290 rs12042319 0.51 0.9 1 hCV31145250 rs10889353 hCV31145291 rs11207995 0.51 0.9 0.9789 hCV31145250 rs10889353 hCV31145298 rs11207992 0.51 0.9 1 hCV31145250 rs10889353 hCV31145302 rs12116574 0.51 0.9 1 hCV31145250 rs10889353 hCV31145332 rs11207981 0.51 0.9 0.9538 hCV31145250 rs10889353 hCV3122390 rs1748200 0.51 0.9 0.959 hCV31145250 rs10889353 hCV316299 rs1168026 0.51 0.9 0.959 hCV31145250 rs10889353 hCV316303 rs1168031 0.51 0.9 0.9586 hCV31145250 rs10889353 hCV32220452 rs12090886 0.51 0.9 1 hCV31145250 rs10889353 hCV32220453 rs10889337 0.51 0.9 0.9585 hCV31145250 rs10889353 hCV32220467 rs10889333 0.51 0.9 1 hCV31145250 rs10889353 hCV32220469 rs10889332 0.51 0.9 0.979 hCV31145250 rs10889353 hCV32220470 rs11207974 0.51 0.9 0.959 hCV31145250 rs10889353 hCV32220491 rs11577840 0.51 0.9 0.9586 hCV31145250 rs10889353 hCV32220495 rs11207969 0.51 0.9 0.979 hCV31145250 rs10889353 hCV408090 rs1183260 0.51 0.9 0.9566 hCV31145250 rs10889353 hCV445207 rs1627591 0.51 0.9 0.959 hCV31145250 rs10889353 hCV71419 rs2131925 0.51 0.9 0.959 hCV31145250 rs10889353 hCV857102 rs624660 0.51 0.9 0.979 hCV31145250 rs10889353 hCV857103 rs636497 0.51 0.9 0.9577 hCV31145250 rs10889353 hCV857104 rs636523 0.51 0.9 1 hCV31145250 rs10889353 hCV857108 rs597078 0.51 0.9 0.958 hCV31145250 rs10889353 hCV857109 rs597470 0.51 0.9 0.959 hCV31145250 rs10889353 hCV857110 rs583609 0.51 0.9 0.979 hCV31145250 rs10889353 hCV857121 rs642845 0.51 0.9 0.958 hCV31145250 rs10889353 hCV857122 rs656297 0.51 0.9 0.979 hCV31145250 rs10889353 hCV857123 rs638305 0.51 0.9 0.959 hCV31145250 rs10889353 hCV857127 rs631106 0.51 0.9 0.9577 hCV31145250 rs10889353 hCV9508668 rs1781195 0.51 0.9 0.979 hCV31145250 rs10889353 hCV9581062 rs998403 0.51 0.9 1 hCV31145250 rs10889353 hCV9581570 rs1168036 0.51 0.9 1 hCV31145250 rs10889353 hCV9581571 rs1002687 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9581580 rs1168032 0.51 0.9 0.958 hCV31145250 rs10889353 hCV9581581 rs1168030 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9581590 rs1168018 0.51 0.9 0.9789 hCV31145250 rs10889353 hCV9581606 rs1168022 0.51 0.9 0.9558 hCV31145250 rs10889353 hCV9581615 rs1748201 0.51 0.9 0.9789 hCV31145250 rs10889353 hCV9581635 rs1748195 0.51 0.9 0.979 hCV31145250 rs10889353 hCV9581636 rs3850634 0.51 0.9 1 hCV31145250 rs10889353 hCV9581680 rs1748197 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9581691 rs1570694 0.51 0.9 1 hCV31145250 rs10889353 hCV9583244 rs783291 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9588770 rs1007205 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9588793 rs1168009 0.51 0.9 0.9365 hCV31145250 rs10889353 hCV9588794 rs1168010 0.51 0.9 0.936 hCV31145250 rs10889353 hCV9588829 rs1781212 0.51 0.9 0.959 hCV31145250 rs10889353 hCV9588850 rs1168013 0.51 0.9 0.979 hCV31145250 rs10889353 hCV9588862 rs995000 0.51 0.9 1 hCV31145250 rs10889353 hCV9588875 rs1168086 0.51 0.9 0.9551 hCV31145250 rs10889353 hCV9588886 rs1168089 0.51 0.9 0.979 hCV31145250 rs10889353 hCV9588930 rs1168099 0.51 0.9 0.979 hCV31145250 rs10889353 hCV9588985 rs1168124 0.51 0.9 0.959 hCV31145250 rs10889353 hDV75176134 rs1781221 0.51 0.9 0.959 hCV31161091 rs3127573 hCV16149755 rs2183470 0.51 0.665154887 0.776 hCV31161091 rs3127573 hCV27397381 rs3120149 0.51 0.665154887 0.7457 hCV31161091 rs3127573 hCV27403525 rs3119309 0.51 0.665154887 0.9549 hCV31161091 rs3127573 hCV27459536 rs3119310 0.51 0.665154887 1 hCV31161091 rs3127573 hCV27460260 rs3119311 0.51 0.665154887 0.9549 hCV31161091 rs3127573 hCV27461119 rs3125056 0.51 0.665154887 0.7 hCV31161091 rs3127573 hCV27462007 rs3127578 0.51 0.665154887 1 hCV31161091 rs3127573 hCV27464241 rs3125052 0.51 0.665154887 0.776 hCV31161091 rs3127573 hCV27464790 rs3127591 0.51 0.665154887 0.7283 hCV31161091 rs3127573 hCV27517953 rs3798156 0.51 0.665154887 0.6692 hCV31161091 rs3127573 hCV30977817 rs3106168 0.51 0.665154887 0.7755 hCV31161091 rs3127573 hCV30977839 rs3120140 0.51 0.665154887 0.8656 hCV31161091 rs3127573 hCV30977855 rs3103350 0.51 0.665154887 0.776 hCV31161091 rs3127573 hCV30977859 rs12209517 0.51 0.665154887 0.8649 hCV31161091 rs3127573 hCV3111820 rs3127572 0.51 0.665154887 1 hCV31161091 rs3127573 hCV31605072 rs12206585 0.51 0.665154887 0.7457 hCV31161091 rs3127573 hCV31605081 rs12203303 0.51 0.665154887 0.7833 hCV31161091 rs3127573 hDV71058825 rs7757336 0.51 0.665154887 0.6683 hCV31161091 rs3127573 hDV71669191 rs3127586 0.51 0.665154887 0.8397 hCV31161091 rs3127573 hDV71967259 rs7756836 0.51 0.665154887 0.9549 hCV31161091 rs3127573 hDV75428625 rs3106167 0.51 0.665154887 0.776 hCV31161091 rs3127573 hDV75428626 rs3106170 0.51 0.665154887 0.7452 hCV31161091 rs3127573 hDV75428628 rs3106172 0.51 0.665154887 0.816 hCV31161091 rs3127573 hDV75431938 rs3120151 0.51 0.665154887 0.776 hCV31161091 rs3127573 hDV75433616 rs3125049 0.51 0.665154887 0.72 hCV31237961 rs11950562 hCV26479157 rs2631360 0.51 0.9 1 hCV31237961 rs11950562 hCV28006893 rs4705938 0.51 0.9 1 hCV31237961 rs11950562 hCV29828916 rs10058074 0.51 0.9 1 hCV31237961 rs11950562 hDV70978086 rs17622208 0.51 0.9 1 hCV3135085 rs10795446 hCV11453231 rs12764449 0.51 0.9 1 hCV3135085 rs10795446 hCV26740575 rs12263745 0.51 0.9 0.9603 hCV3135085 rs10795446 hCV2822668 rs10904880 0.51 0.9 0.9602 hCV3135085 rs10795446 hCV2822671 rs7900434 0.51 0.9 0.9794 hCV3135085 rs10795446 hCV2822672 rs7900428 0.51 0.9 0.9169 hCV3135085 rs10795446 hCV2822673 rs7900190 0.51 0.9 0.9793 hCV3135085 rs10795446 hCV3135082 rs7921322 0.51 0.9 1 hCV3135085 rs10795446 hCV3135091 rs4748355 0.51 0.9 0.9598 hCV31528409 rs7635061 hCV251046 rs4075158 0.51 0.9 1 hCV31528409 rs7635061 hCV31746376 rs12494136 0.51 0.9 1 hCV31528409 rs7635061 hCV439262 rs8179973 0.51 0.9 0.9109 hCV31528409 rs7635061 hCV439263 rs8180032 0.51 0.9 0.9051 hCV3168675 rs469930 hCV984679 rs467650 0.51 0.9 0.9781 hCV3168675 rs469930 hCV984683 rs468238 0.51 0.9 1 hCV3168675 rs469930 hCV984684 rs154197 0.51 0.9 1 hCV3170445 rs272893 hCV1173593 rs274567 0.51 0.9 1 hCV3170445 rs272893 hCV1173600 rs274562 0.51 0.9 1 hCV3170445 rs272893 hCV1173605 rs274559 0.51 0.9 0.9612 hCV3170445 rs272893 hCV2390950 rs274546 0.51 0.9 0.9804 hCV3170445 rs272893 hCV2390957 rs272894 0.51 0.9 0.9612 hCV3170445 rs272893 hCV26479192 rs272865 0.51 0.9 0.922 hCV3170445 rs272893 hCV2843383 rs2631370 0.51 0.9 0.9612 hCV3170445 rs272893 hCV2843392 rs272884 0.51 0.9 0.9612 hCV3170445 rs272893 hCV2843394 rs272881 0.51 0.9 0.9612 hCV3170445 rs272893 hCV2843395 rs272879 0.51 0.9 0.96 hCV3170445 rs272893 hCV2950035 rs419291 0.51 0.9 0.9804 hCV3170445 rs272893 hCV3170430 rs270613 0.51 0.9 0.9408 hCV3170445 rs272893 hCV3170440 rs270605 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3170442 rs273914 0.51 0.9 0.9097 hCV3170445 rs272893 hCV3170446 rs272889 0.51 0.9 1 hCV3170445 rs272893 hCV3170448 rs272886 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3170453 rs272875 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3170454 rs272874 0.51 0.9 1 hCV3170445 rs272893 hCV3170461 rs272869 0.51 0.9 1 hCV3170445 rs272893 hCV3170463 rs4705933 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3170466 rs272867 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3281569 rs272842 0.51 0.9 0.9612 hCV3170445 rs272893 hCV3281570 rs270602 0.51 0.9 1 hCV3170445 rs272893 hCV559622 rs274561 0.51 0.9 1 hCV3170445 rs272893 hCV559623 rs274560 0.51 0.9 1 hCV3170445 rs272893 hCV559624 rs274558 0.51 0.9 0.9612 hCV3170445 rs272893 hCV559625 rs274557 0.51 0.9 0.9612 hCV3170445 rs272893 hCV9157871 rs272860 0.51 0.9 0.9589 hCV3170445 rs272893 hCV9158012 rs273913 0.51 0.9 0.9612 hCV3170459 rs1050152 hCV15849790 rs2188962 0.51 0.9 0.9412 hCV3170459 rs1050152 hCV2554569 rs11951091 0.51 0.9 0.9644 hCV3170459 rs1050152 hCV2554615 rs2522057 0.51 0.9 0.9037 hCV3170459 rs1050152 hCV2554620 rs2248116 0.51 0.9 0.9027 hCV3170459 rs1050152 hCV31237908 rs12515180 0.51 0.9 0.9624 hCV3170459 rs1050152 hCV31237910 rs12521868 0.51 0.9 0.9409 hCV3170459 rs1050152 hCV3281563 rs11741255 0.51 0.9 0.9226 hCV3170459 rs1050152 hDV70978119 rs17622378 0.51 0.9 0.9639 hCV3201490 rs1321195 hCV103951 rs6455688 0.51 0.325832601 0.3951 hCV3201490 rs1321195 hCV103952 rs6923877 0.51 0.325832601 0.3951 hCV3201490 rs1321195 hCV11284288 rs9457946 0.51 0.325832601 0.3442 hCV3201490 rs1321195 hCV11285578 rs6926458 0.51 0.325832601 0.6014 hCV3201490 rs1321195 hCV11846435 rs6929299 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV1550871 rs9355295 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV15975022 rs2314852 0.51 0.325832601 0.3961 hCV3201490 rs1321195 hCV207123 rs7771801 0.51 0.325832601 0.3429 hCV3201490 rs1321195 hCV207127 rs7453899 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV207128 rs6455689 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV243055 rs10945682 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV249898 rs9456552 0.51 0.325832601 0.3355 hCV3201490 rs1321195 hCV25927459 rs3798221 0.51 0.325832601 0.6526 hCV3201490 rs1321195 hCV25929408 rs7765781 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV25929478 rs7765803 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV26272388 rs7770685 0.51 0.325832601 0.6129 hCV3201490 rs1321195 hCV26272389 rs7760585 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV27422538 rs6940254 0.51 0.325832601 0.6 hCV3201490 rs1321195 hCV27422546 rs7761377 0.51 0.325832601 0.3287 hCV3201490 rs1321195 hCV27422554 rs6923917 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV27422556 rs9355814 0.51 0.325832601 0.3325 hCV3201490 rs1321195 hCV27422557 rs9355813 0.51 0.325832601 0.3283 hCV3201490 rs1321195 hCV27422565 rs13202636 0.51 0.325832601 0.6129 hCV3201490 rs1321195 hCV29322781 rs6921516 0.51 0.325832601 0.3635 hCV3201490 rs1321195 hCV29546641 rs9365171 0.51 0.325832601 0.3342 hCV3201490 rs1321195 hCV29998162 rs9457943 0.51 0.325832601 0.3554 hCV3201490 rs1321195 hCV31882494 rs12175867 0.51 0.325832601 0.6 hCV3201490 rs1321195 hCV3201494 rs1367209 0.51 0.325832601 0.4687 hCV3201490 rs1321195 hCV3201495 rs1367210 0.51 0.325832601 1 hCV3201490 rs1321195 hCV3201497 rs1321196 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV8701273 rs783148 0.51 0.325832601 1 hCV3201490 rs1321195 hCV8710161 rs1740428 0.51 0.325832601 0.3278 hCV3201490 rs1321195 hCV8710162 rs1367211 0.51 0.325832601 0.4687 hCV32055474 rs10864359 hCV11398434 rs1812457 0.51 0.5160794 1 hCV32055474 rs10864359 hCV11398437 rs1817367 0.51 0.5160794 0.8987 hCV32055474 rs10864359 hCV11675962 rs10746481 0.51 0.5160794 0.9345 hCV32055474 rs10864359 hCV1188731 rs4908514 0.51 0.5160794 0.7979 hCV32055474 rs10864359 hCV1188735 rs10864366 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV15882429 rs2289732 0.51 0.5160794 0.5747 hCV32055474 rs10864359 hCV15932991 rs2781067 0.51 0.5160794 0.5621 hCV32055474 rs10864359 hCV27157507 rs6664000 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV27157524 rs6577531 0.51 0.5160794 0.7394 hCV32055474 rs10864359 hCV2741759 rs11121179 0.51 0.5160794 0.5606 hCV32055474 rs10864359 hCV27884601 rs4908776 0.51 0.5160794 0.7973 hCV32055474 rs10864359 hCV27958354 rs4908762 0.51 0.5160794 0.8778 hCV32055474 rs10864359 hCV28023091 rs4908773 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV29368919 rs4908513 0.51 0.5160794 0.7979 hCV32055474 rs10864359 hCV2943451 rs902355 0.51 0.5160794 0.6535 hCV32055474 rs10864359 hCV2943853 rs301793 0.51 0.5160794 0.5747 hCV32055474 rs10864359 hCV2966436 rs11121174 0.51 0.5160794 0.5747 hCV32055474 rs10864359 hCV2966437 rs11580417 0.51 0.5160794 0.5747 hCV32055474 rs10864359 hCV2966441 rs6684863 0.51 0.5160794 0.5747 hCV32055474 rs10864359 hCV2966444 rs11121171 0.51 0.5160794 0.6208 hCV32055474 rs10864359 hCV29819064 rs6698079 0.51 0.5160794 1 hCV32055474 rs10864359 hCV2987250 rs301810 0.51 0.5160794 0.665 hCV32055474 rs10864359 hCV29873524 rs7533113 0.51 0.5160794 0.7979 hCV32055474 rs10864359 hCV29873526 rs6697997 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV29945430 rs7517436 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV30035535 rs7518204 0.51 0.5160794 0.7971 hCV32055474 rs10864359 hCV30125699 rs4581300 0.51 0.5160794 0.8169 hCV32055474 rs10864359 hCV30143725 rs6690050 0.51 0.5160794 0.9345 hCV32055474 rs10864359 hCV30467730 rs6702457 0.51 0.5160794 0.9345 hCV32055474 rs10864359 hCV3086930 rs6658881 0.51 0.5160794 0.85 hCV32055474 rs10864359 hCV3086932 rs7533442 0.51 0.5160794 0.85 hCV32055474 rs10864359 hCV3086950 rs4908771 0.51 0.5160794 0.9345 hCV32055474 rs10864359 hCV3086961 rs6703577 0.51 0.5160794 0.9379 hCV32055474 rs10864359 hCV3086971 rs6679948 0.51 0.5160794 1 hCV32055474 rs10864359 hCV3086972 rs6688329 0.51 0.5160794 1 hCV32055474 rs10864359 hCV3086998 rs7530863 0.51 0.5160794 0.8778 hCV32055474 rs10864359 hCV3087000 rs1463055 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV3087003 rs6577500 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV3087015 rs11121198 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV3087016 rs2297867 0.51 0.5160794 0.85 hCV32055474 rs10864359 hCV32055284 rs12079653 0.51 0.5160794 0.6676 hCV32055474 rs10864359 hCV32055470 rs6577506 0.51 0.5160794 0.9379 hCV32055474 rs10864359 hCV32055477 rs10779705 0.51 0.5160794 1 hCV32055474 rs10864359 hCV32055527 rs10864364 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV32055548 rs11121197 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV32055579 rs6577522 0.51 0.5160794 0.7977 hCV32055474 rs10864359 hCV32055595 rs6577524 0.51 0.5160794 0.7979 hCV32055474 rs10864359 hCV32055596 rs6577525 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV32055625 rs6678590 0.51 0.5160794 0.7419 hCV32055474 rs10864359 hCV32055637 rs6577532 0.51 0.5160794 0.5364 hCV32055474 rs10864359 hCV32055677 rs10864355 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV529178 rs301811 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV529182 rs301800 0.51 0.5160794 0.5869 hCV32055474 rs10864359 hCV597227 rs301809 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV597229 rs301785 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV877241 rs301788 0.51 0.5160794 0.5606 hCV32055474 rs10864359 hCV8823713 rs1472228 0.51 0.5160794 0.6717 hCV32055474 rs10864359 hCV8824288 rs910582 0.51 0.5160794 0.8759 hCV32055474 rs10864359 hCV8824394 rs1443929 0.51 0.5160794 0.5606 hCV32055474 rs10864359 hCV8824424 rs1058790 0.51 0.5160794 0.6208 hCV32055474 rs10864359 hCV8824425 rs1058791 0.51 0.5160794 0.5324 hCV32055474 rs10864359 hCV8881145 rs1038008 0.51 0.5160794 1 hCV32055474 rs10864359 hCV8881146 rs1463054 0.51 0.5160794 1 hCV32055474 rs10864359 hCV8881157 rs1535158 0.51 0.5160794 1 hCV32055474 rs10864359 hCV8881161 rs926951 0.51 0.5160794 0.8778 hCV32055477 rs10779705 hCV11398434 rs1812457 0.51 0.519194102 1 hCV32055477 rs10779705 hCV11398437 rs1817367 0.51 0.519194102 1 hCV32055477 rs10779705 hCV11675962 rs10746481 0.51 0.519194102 0.9381 hCV32055477 rs10779705 hCV1188731 rs4908514 0.51 0.519194102 0.8094 hCV32055477 rs10779705 hCV1188735 rs10864366 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV15882429 rs2289732 0.51 0.519194102 0.5975 hCV32055477 rs10779705 hCV15932991 rs2781067 0.51 0.519194102 0.5861 hCV32055477 rs10779705 hCV27157507 rs6664000 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV27157524 rs6577531 0.51 0.519194102 0.7539 hCV32055477 rs10779705 hCV2741759 rs11121179 0.51 0.519194102 0.5747 hCV32055477 rs10779705 hCV27884601 rs4908776 0.51 0.519194102 0.8089 hCV32055477 rs10779705 hCV27958354 rs4908762 0.51 0.519194102 0.8759 hCV32055477 rs10779705 hCV28023091 rs4908773 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV29368919 rs4908513 0.51 0.519194102 0.8094 hCV32055477 rs10779705 hCV2943451 rs902355 0.51 0.519194102 0.6736 hCV32055477 rs10779705 hCV2943853 rs301793 0.51 0.519194102 0.5975 hCV32055477 rs10779705 hCV2966436 rs11121174 0.51 0.519194102 0.5975 hCV32055477 rs10779705 hCV2966437 rs11580417 0.51 0.519194102 0.5975 hCV32055477 rs10779705 hCV2966441 rs6684863 0.51 0.519194102 0.5975 hCV32055477 rs10779705 hCV2966444 rs11121171 0.51 0.519194102 0.6417 hCV32055477 rs10779705 hCV29819064 rs6698079 0.51 0.519194102 1 hCV32055477 rs10779705 hCV2987250 rs301810 0.51 0.519194102 0.6812 hCV32055477 rs10779705 hCV29873524 rs7533113 0.51 0.519194102 0.8094 hCV32055477 rs10779705 hCV29873526 rs6697997 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV29945430 rs7517436 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV30035535 rs7518204 0.51 0.519194102 0.8087 hCV32055477 rs10779705 hCV30125699 rs4581300 0.51 0.519194102 0.8759 hCV32055477 rs10779705 hCV30143725 rs6690050 0.51 0.519194102 0.9381 hCV32055477 rs10779705 hCV30467730 rs6702457 0.51 0.519194102 0.9381 hCV32055477 rs10779705 hCV3086930 rs6658881 0.51 0.519194102 0.9345 hCV32055477 rs10779705 hCV3086932 rs7533442 0.51 0.519194102 0.9345 hCV32055477 rs10779705 hCV3086950 rs4908771 0.51 0.519194102 0.9381 hCV32055477 rs10779705 hCV3086961 rs6703577 0.51 0.519194102 1 hCV32055477 rs10779705 hCV3086971 rs6679948 0.51 0.519194102 1 hCV32055477 rs10779705 hCV3086972 rs6688329 0.51 0.519194102 1 hCV32055477 rs10779705 hCV3086998 rs7530863 0.51 0.519194102 0.8759 hCV32055477 rs10779705 hCV3087000 rs1463055 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV3087003 rs6577500 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV3087015 rs11121198 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV3087016 rs2297867 0.51 0.519194102 0.8759 hCV32055477 rs10779705 hCV32055284 rs12079653 0.51 0.519194102 0.6858 hCV32055477 rs10779705 hCV32055470 rs6577506 0.51 0.519194102 1 hCV32055477 rs10779705 hCV32055474 rs10864359 0.51 0.519194102 1 hCV32055477 rs10779705 hCV32055527 rs10864364 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV32055548 rs11121197 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV32055579 rs6577522 0.51 0.519194102 0.8092 hCV32055477 rs10779705 hCV32055595 rs6577524 0.51 0.519194102 0.8094 hCV32055477 rs10779705 hCV32055596 rs6577525 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV32055625 rs6678590 0.51 0.519194102 0.7684 hCV32055477 rs10779705 hCV32055637 rs6577532 0.51 0.519194102 0.7394 hCV32055477 rs10779705 hCV32055662 rs6677249 0.51 0.519194102 0.5758 hCV32055477 rs10779705 hCV32055677 rs10864355 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV529178 rs301811 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV529182 rs301800 0.51 0.519194102 0.6217 hCV32055477 rs10779705 hCV597227 rs301809 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV597229 rs301785 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV877241 rs301788 0.51 0.519194102 0.5747 hCV32055477 rs10779705 hCV8823713 rs1472228 0.51 0.519194102 0.7979 hCV32055477 rs10779705 hCV8824288 rs910582 0.51 0.519194102 0.8824 hCV32055477 rs10779705 hCV8824394 rs1443929 0.51 0.519194102 0.5747 hCV32055477 rs10779705 hCV8824424 rs1058790 0.51 0.519194102 0.6417 hCV32055477 rs10779705 hCV8824425 rs1058791 0.51 0.519194102 0.62 hCV32055477 rs10779705 hCV8881145 rs1038008 0.51 0.519194102 1 hCV32055477 rs10779705 hCV8881146 rs1463054 0.51 0.519194102 1 hCV32055477 rs10779705 hCV8881157 rs1535158 0.51 0.519194102 1 hCV32055477 rs10779705 hCV8881161 rs926951 0.51 0.519194102 0.8759 hCV32055527 rs10864364 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hCV32055527 rs10864364 hCV27157524 rs6577531 0.51 0.494565781 0.9314 hCV32055527 rs10864364 hCV2741759 rs11121179 0.51 0.494565781 0.6713 hCV32055527 rs10864364 hCV27474399 rs3753275 0.51 0.494565781 0.5807 hCV32055527 rs10864364 hCV27884601 rs4908776 0.51 0.494565781 1 hCV32055527 rs10864364 hCV27958354 rs4908762 0.51 0.494565781 0.6717 hCV32055527 rs10864364 hCV28023091 rs4908773 0.51 0.494565781 1 hCV32055527 rs10864364 hCV29368919 rs4908513 0.51 0.494565781 1 hCV32055527 rs10864364 hCV2943451 rs902355 0.51 0.494565781 0.7098 hCV32055527 rs10864364 hCV2943853 rs301793 0.51 0.494565781 0.6247 hCV32055527 rs10864364 hCV2966436 rs11121174 0.51 0.494565781 0.6247 hCV32055527 rs10864364 hCV2966437 rs11580417 0.51 0.494565781 0.6247 hCV32055527 rs10864364 hCV2966441 rs6684863 0.51 0.494565781 0.6247 hCV32055527 rs10864364 hCV2966444 rs11121171 0.51 0.494565781 0.6727 hCV32055527 rs10864364 hCV29819064 rs6698079 0.51 0.494565781 0.7458 hCV32055527 rs10864364 hCV2987250 rs301810 0.51 0.494565781 0.5105 hCV32055527 rs10864364 hCV29873524 rs7533113 0.51 0.494565781 1 hCV32055527 rs10864364 hCV29873526 rs6697997 0.51 0.494565781 0.6952 hCV32055527 rs10864364 hCV29945430 rs7517436 0.51 0.494565781 1 hCV32055527 rs10864364 hCV30035535 rs7518204 0.51 0.494565781 1 hCV32055527 rs10864364 hCV30125699 rs4581300 0.51 0.494565781 0.6067 hCV32055527 rs10864364 hCV30143725 rs6690050 0.51 0.494565781 0.7437 hCV32055527 rs10864364 hCV30467730 rs6702457 0.51 0.494565781 0.8704 hCV32055527 rs10864364 hCV3086930 rs6658881 0.51 0.494565781 0.8213 hCV32055527 rs10864364 hCV3086932 rs7533442 0.51 0.494565781 0.8213 hCV32055527 rs10864364 hCV3086950 rs4908771 0.51 0.494565781 0.8704 hCV32055527 rs10864364 hCV3086961 rs6703577 0.51 0.494565781 0.7188 hCV32055527 rs10864364 hCV3086971 rs6679948 0.51 0.494565781 0.7979 hCV32055527 rs10864364 hCV3086972 rs6688329 0.51 0.494565781 0.8568 hCV32055527 rs10864364 hCV3086998 rs7530863 0.51 0.494565781 0.6717 hCV32055527 rs10864364 hCV3087000 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rs10864364 hCV32055677 rs10864355 0.51 0.494565781 0.6952 hCV32055527 rs10864364 hCV529178 rs301811 0.51 0.494565781 0.6949 hCV32055527 rs10864364 hCV529182 rs301800 0.51 0.494565781 0.6998 hCV32055527 rs10864364 hCV597227 rs301809 0.51 0.494565781 0.6952 hCV32055527 rs10864364 hCV597229 rs301785 0.51 0.494565781 0.6952 hCV32055527 rs10864364 hCV877241 rs301788 0.51 0.494565781 0.6713 hCV32055527 rs10864364 hCV8823713 rs1472228 0.51 0.494565781 1 hCV32055527 rs10864364 hCV8824244 rs1006950 0.51 0.494565781 0.574 hCV32055527 rs10864364 hCV8824248 rs1543711 0.51 0.494565781 0.6126 hCV32055527 rs10864364 hCV8824288 rs910582 0.51 0.494565781 0.6952 hCV32055527 rs10864364 hCV8824394 rs1443929 0.51 0.494565781 0.6713 hCV32055527 rs10864364 hCV8824424 rs1058790 0.51 0.494565781 0.6727 hCV32055527 rs10864364 hCV8824425 rs1058791 0.51 0.494565781 0.6383 hCV32055527 rs10864364 hCV8881145 rs1038008 0.51 0.494565781 0.7979 hCV32055527 rs10864364 hCV8881146 rs1463054 0.51 0.494565781 0.8032 hCV32055527 rs10864364 hCV8881157 rs1535158 0.51 0.494565781 0.7979 hCV32055527 rs10864364 hCV8881161 rs926951 0.51 0.494565781 0.6717 hCV32055595 rs6577524 hCV11398434 rs1812457 0.51 0.496166123 0.8094 hCV32055595 rs6577524 hCV11398437 rs1817367 0.51 0.496166123 0.7755 hCV32055595 rs6577524 hCV11675962 rs10746481 0.51 0.496166123 0.8774 hCV32055595 rs6577524 hCV1188659 rs3820037 0.51 0.496166123 0.5968 hCV32055595 rs6577524 hCV1188660 rs6660137 0.51 0.496166123 0.6126 hCV32055595 rs6577524 hCV1188664 rs2765511 0.51 0.496166123 0.6312 hCV32055595 rs6577524 hCV1188665 rs2781060 0.51 0.496166123 0.6541 hCV32055595 rs6577524 hCV1188676 rs11121247 0.51 0.496166123 0.6126 hCV32055595 rs6577524 hCV1188731 rs4908514 0.51 0.496166123 1 hCV32055595 rs6577524 hCV1188735 rs10864366 0.51 0.496166123 1 hCV32055595 rs6577524 hCV12040675 rs2038904 0.51 0.496166123 0.6312 hCV32055595 rs6577524 hCV15882429 rs2289732 0.51 0.496166123 0.6452 hCV32055595 rs6577524 hCV15932991 rs2781067 0.51 0.496166123 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0.6452 hCV32055595 rs6577524 hCV2966444 rs11121171 0.51 0.496166123 0.6911 hCV32055595 rs6577524 hCV29819064 rs6698079 0.51 0.496166123 0.7479 hCV32055595 rs6577524 hCV2987250 rs301810 0.51 0.496166123 0.6312 hCV32055595 rs6577524 hCV29873524 rs7533113 0.51 0.496166123 1 hCV32055595 rs6577524 hCV29873526 rs6697997 0.51 0.496166123 0.7112 hCV32055595 rs6577524 hCV29945430 rs7517436 0.51 0.496166123 1 hCV32055595 rs6577524 hCV30035535 rs7518204 0.51 0.496166123 1 hCV32055595 rs6577524 hCV30125699 rs4581300 0.51 0.496166123 0.6952 hCV32055595 rs6577524 hCV30143725 rs6690050 0.51 0.496166123 0.7577 hCV32055595 rs6577524 hCV30467730 rs6702457 0.51 0.496166123 0.8774 hCV32055595 rs6577524 hCV3086930 rs6658881 0.51 0.496166123 0.8704 hCV32055595 rs6577524 hCV3086932 rs7533442 0.51 0.496166123 0.8704 hCV32055595 rs6577524 hCV3086950 rs4908771 0.51 0.496166123 0.8774 hCV32055595 rs6577524 hCV3086961 rs6703577 0.51 0.496166123 0.7979 hCV32055595 rs6577524 hCV3086971 rs6679948 0.51 0.496166123 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rs4745688 0.51 0.430305154 0.8953 hCV472000 rs3002374 hCV30442834 rs10481782 0.51 0.430305154 0.8903 hCV472000 rs3002374 hCV320070 rs13286409 0.51 0.430305154 0.8094 hCV472000 rs3002374 hCV446684 rs2252949 0.51 0.430305154 1 hCV472000 rs3002374 hCV447339 rs2486450 0.51 0.430305154 0.8662 hCV472000 rs3002374 hCV457907 rs3002376 0.51 0.430305154 0.9002 hCV472000 rs3002374 hCV500457 rs7018554 0.51 0.430305154 0.9474 hCV472000 rs3002374 hCV76127 rs9411192 0.51 0.430305154 0.9002 hCV472000 rs3002374 hCV85712 rs946541 0.51 0.430305154 0.9474 hCV487868 rs6439132 hCV11230071 rs12490685 0.51 0.9 1 hCV487868 rs6439132 hCV26427875 rs6803892 0.51 0.9 1 hCV487868 rs6439132 hCV29665677 rs7631797 0.51 0.9 1 hCV487868 rs6439132 hCV30387127 rs7629705 0.51 0.9 0.9255 hCV529178 rs301811 hCV11398434 rs1812457 0.51 0.536691312 0.8824 hCV529178 rs301811 hCV11398437 rs1817367 0.51 0.536691312 0.8638 hCV529178 rs301811 hCV11675962 rs10746481 0.51 0.536691312 0.8246 hCV529178 rs301811 hCV1188731 rs4908514 0.51 0.536691312 0.7109 hCV529178 rs301811 hCV1188735 rs10864366 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV15882429 rs2289732 0.51 0.536691312 0.7149 hCV529178 rs301811 hCV25996298 rs7535752 0.51 0.536691312 0.58 hCV529178 rs301811 hCV27157507 rs6664000 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV27157524 rs6577531 0.51 0.536691312 0.659 hCV529178 rs301811 hCV2741759 rs11121179 0.51 0.536691312 0.6991 hCV529178 rs301811 hCV27474399 rs3753275 0.51 0.536691312 0.5818 hCV529178 rs301811 hCV27884601 rs4908776 0.51 0.536691312 0.7101 hCV529178 rs301811 hCV27958354 rs4908762 0.51 0.536691312 1 hCV529178 rs301811 hCV28023091 rs4908773 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV29368919 rs4908513 0.51 0.536691312 0.7109 hCV529178 rs301811 hCV2943451 rs902355 0.51 0.536691312 0.7442 hCV529178 rs301811 hCV2943853 rs301793 0.51 0.536691312 0.7149 hCV529178 rs301811 hCV2966436 rs11121174 0.51 0.536691312 0.7149 hCV529178 rs301811 hCV2966437 rs11580417 0.51 0.536691312 0.7149 hCV529178 rs301811 hCV2966441 rs6684863 0.51 0.536691312 0.7149 hCV529178 rs301811 hCV2966444 rs11121171 0.51 0.536691312 0.767 hCV529178 rs301811 hCV29819064 rs6698079 0.51 0.536691312 0.8488 hCV529178 rs301811 hCV2987250 rs301810 0.51 0.536691312 0.8909 hCV529178 rs301811 hCV29873524 rs7533113 0.51 0.536691312 0.7109 hCV529178 rs301811 hCV29873526 rs6697997 0.51 0.536691312 1 hCV529178 rs301811 hCV29945430 rs7517436 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV30035535 rs7518204 0.51 0.536691312 0.7098 hCV529178 rs301811 hCV30125699 rs4581300 0.51 0.536691312 1 hCV529178 rs301811 hCV30143725 rs6690050 0.51 0.536691312 0.8246 hCV529178 rs301811 hCV30467730 rs6702457 0.51 0.536691312 0.8246 hCV529178 rs301811 hCV3086930 rs6658881 0.51 0.536691312 0.8149 hCV529178 rs301811 hCV3086932 rs7533442 0.51 0.536691312 0.8149 hCV529178 rs301811 hCV3086950 rs4908771 0.51 0.536691312 0.8246 hCV529178 rs301811 hCV3086961 rs6703577 0.51 0.536691312 0.8759 hCV529178 rs301811 hCV3086971 rs6679948 0.51 0.536691312 0.8824 hCV529178 rs301811 hCV3086972 rs6688329 0.51 0.536691312 0.8759 hCV529178 rs301811 hCV3086998 rs7530863 0.51 0.536691312 1 hCV529178 rs301811 hCV3087000 rs1463055 0.51 0.536691312 1 hCV529178 rs301811 hCV3087003 rs6577500 0.51 0.536691312 1 hCV529178 rs301811 hCV3087015 rs11121198 0.51 0.536691312 1 hCV529178 rs301811 hCV3087016 rs2297867 0.51 0.536691312 1 hCV529178 rs301811 hCV32055284 rs12079653 0.51 0.536691312 0.6985 hCV529178 rs301811 hCV32055470 rs6577506 0.51 0.536691312 0.8759 hCV529178 rs301811 hCV32055474 rs10864359 0.51 0.536691312 0.8759 hCV529178 rs301811 hCV32055477 rs10779705 0.51 0.536691312 0.8824 hCV529178 rs301811 hCV32055527 rs10864364 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV32055548 rs11121197 0.51 0.536691312 1 hCV529178 rs301811 hCV32055579 rs6577522 0.51 0.536691312 0.7106 hCV529178 rs301811 hCV32055595 rs6577524 0.51 0.536691312 0.7109 hCV529178 rs301811 hCV32055596 rs6577525 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV32055625 rs6678590 0.51 0.536691312 0.6074 hCV529178 rs301811 hCV32055637 rs6577532 0.51 0.536691312 0.6401 hCV529178 rs301811 hCV32055677 rs10864355 0.51 0.536691312 1 hCV529178 rs301811 hCV529182 rs301800 0.51 0.536691312 0.7543 hCV529178 rs301811 hCV597227 rs301809 0.51 0.536691312 1 hCV529178 rs301811 hCV597229 rs301785 0.51 0.536691312 1 hCV529178 rs301811 hCV877241 rs301788 0.51 0.536691312 0.6991 hCV529178 rs301811 hCV8823713 rs1472228 0.51 0.536691312 0.6949 hCV529178 rs301811 hCV8824288 rs910582 0.51 0.536691312 1 hCV529178 rs301811 hCV8824394 rs1443929 0.51 0.536691312 0.6991 hCV529178 rs301811 hCV8824424 rs1058790 0.51 0.536691312 0.767 hCV529178 rs301811 hCV8824425 rs1058791 0.51 0.536691312 0.7538 hCV529178 rs301811 hCV8881145 rs1038008 0.51 0.536691312 0.8824 hCV529178 rs301811 hCV8881146 rs1463054 0.51 0.536691312 0.8271 hCV529178 rs301811 hCV8881157 rs1535158 0.51 0.536691312 0.8824 hCV529178 rs301811 hCV8881161 rs926951 0.51 0.536691312 1 hCV529706 rs428785 hCV1129216 rs370850 0.51 0.9 0.9486 hCV529706 rs428785 hCV1129217 rs416905 0.51 0.9 0.9486 hCV529706 rs428785 hCV1129218 rs420742 0.51 0.9 0.9486 hCV529706 rs428785 hCV11799502 rs392840 0.51 0.9 0.9486 hCV529706 rs428785 hCV529701 rs422381 0.51 0.9 0.9523 hCV529706 rs428785 hCV529703 rs451792 0.51 0.9 0.9523 hCV529706 rs428785 hCV529708 rs445784 0.51 0.9 0.9507 hCV537525 rs197943 hCV15885004 rs2277614 0.51 0.550075489 0.6606 hCV537525 rs197943 hCV2275251 rs197927 0.51 0.550075489 1 hCV537525 rs197943 hCV2275252 rs197928 0.51 0.550075489 1 hCV537525 rs197943 hCV2960488 rs197909 0.51 0.550075489 1 hCV537525 rs197943 hCV7451329 rs197938 0.51 0.550075489 1 hCV549926 rs1057141 hCV16222565 rs2395269 0.51 0.9 0.921 hCV549926 rs1057141 hCV27015215 rs2071482 0.51 0.9 0.9603 hCV549926 rs1057141 hCV2961762 rs12529313 0.51 0.9 1 hCV549926 rs1057141 hCV2961763 rs12527715 0.51 0.9 1 hCV597227 rs301809 hCV11398434 rs1812457 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV11398437 rs1817367 0.51 0.533875411 0.8638 hCV597227 rs301809 hCV11675962 rs10746481 0.51 0.533875411 0.8248 hCV597227 rs301809 hCV1188731 rs4908514 0.51 0.533875411 0.7112 hCV597227 rs301809 hCV1188735 rs10864366 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV15882429 rs2289732 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV25996298 rs7535752 0.51 0.533875411 0.5809 hCV597227 rs301809 hCV27157507 rs6664000 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV27157524 rs6577531 0.51 0.533875411 0.6596 hCV597227 rs301809 hCV2741759 rs11121179 0.51 0.533875411 0.6996 hCV597227 rs301809 hCV27474399 rs3753275 0.51 0.533875411 0.5827 hCV597227 rs301809 hCV27884601 rs4908776 0.51 0.533875411 0.7103 hCV597227 rs301809 hCV27958354 rs4908762 0.51 0.533875411 1 hCV597227 rs301809 hCV28023091 rs4908773 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV29368919 rs4908513 0.51 0.533875411 0.7112 hCV597227 rs301809 hCV2943451 rs902355 0.51 0.533875411 0.7442 hCV597227 rs301809 hCV2943853 rs301793 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV2966436 rs11121174 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV2966437 rs11580417 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV2966441 rs6684863 0.51 0.533875411 0.7153 hCV597227 rs301809 hCV2966444 rs11121171 0.51 0.533875411 0.7672 hCV597227 rs301809 hCV29819064 rs6698079 0.51 0.533875411 0.8488 hCV597227 rs301809 hCV2987250 rs301810 0.51 0.533875411 0.8909 hCV597227 rs301809 hCV29873524 rs7533113 0.51 0.533875411 0.7112 hCV597227 rs301809 hCV29873526 rs6697997 0.51 0.533875411 1 hCV597227 rs301809 hCV29945430 rs7517436 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV30035535 rs7518204 0.51 0.533875411 0.7101 hCV597227 rs301809 hCV30125699 rs4581300 0.51 0.533875411 1 hCV597227 rs301809 hCV30143725 rs6690050 0.51 0.533875411 0.8248 hCV597227 rs301809 hCV30467730 rs6702457 0.51 0.533875411 0.8248 hCV597227 rs301809 hCV3086930 rs6658881 0.51 0.533875411 0.815 hCV597227 rs301809 hCV3086932 rs7533442 0.51 0.533875411 0.815 hCV597227 rs301809 hCV3086950 rs4908771 0.51 0.533875411 0.8248 hCV597227 rs301809 hCV3086961 rs6703577 0.51 0.533875411 0.8759 hCV597227 rs301809 hCV3086971 rs6679948 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV3086972 rs6688329 0.51 0.533875411 0.8759 hCV597227 rs301809 hCV3086998 rs7530863 0.51 0.533875411 1 hCV597227 rs301809 hCV3087000 rs1463055 0.51 0.533875411 1 hCV597227 rs301809 hCV3087003 rs6577500 0.51 0.533875411 1 hCV597227 rs301809 hCV3087015 rs11121198 0.51 0.533875411 1 hCV597227 rs301809 hCV3087016 rs2297867 0.51 0.533875411 1 hCV597227 rs301809 hCV32055284 rs12079653 0.51 0.533875411 0.6985 hCV597227 rs301809 hCV32055470 rs6577506 0.51 0.533875411 0.8759 hCV597227 rs301809 hCV32055474 rs10864359 0.51 0.533875411 0.8759 hCV597227 rs301809 hCV32055477 rs10779705 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV32055527 rs10864364 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV32055548 rs11121197 0.51 0.533875411 1 hCV597227 rs301809 hCV32055579 rs6577522 0.51 0.533875411 0.7109 hCV597227 rs301809 hCV32055595 rs6577524 0.51 0.533875411 0.7112 hCV597227 rs301809 hCV32055596 rs6577525 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV32055625 rs6678590 0.51 0.533875411 0.6074 hCV597227 rs301809 hCV32055637 rs6577532 0.51 0.533875411 0.6408 hCV597227 rs301809 hCV32055677 rs10864355 0.51 0.533875411 1 hCV597227 rs301809 hCV529178 rs301811 0.51 0.533875411 1 hCV597227 rs301809 hCV529182 rs301800 0.51 0.533875411 0.7545 hCV597227 rs301809 hCV597229 rs301785 0.51 0.533875411 1 hCV597227 rs301809 hCV877241 rs301788 0.51 0.533875411 0.6996 hCV597227 rs301809 hCV8823713 rs1472228 0.51 0.533875411 0.6952 hCV597227 rs301809 hCV8824288 rs910582 0.51 0.533875411 1 hCV597227 rs301809 hCV8824394 rs1443929 0.51 0.533875411 0.6996 hCV597227 rs301809 hCV8824424 rs1058790 0.51 0.533875411 0.7672 hCV597227 rs301809 hCV8824425 rs1058791 0.51 0.533875411 0.754 hCV597227 rs301809 hCV8881145 rs1038008 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV8881146 rs1463054 0.51 0.533875411 0.8271 hCV597227 rs301809 hCV8881157 rs1535158 0.51 0.533875411 0.8824 hCV597227 rs301809 hCV8881161 rs926951 0.51 0.533875411 1 hCV598677 rs5370 hCV15870027 rs2071943 0.51 0.9 0.9736 hCV598677 rs5370 hCV7464888 rs1800543 0.51 0.9 0.9732 hCV598677 rs5370 hCV7464890 rs1476046 0.51 0.9 0.9736 hCV601946 rs524802 hCV11467059 rs472226 0.51 0.9 0.9624 hCV601946 rs524802 hCV25994206 rs3745770 0.51 0.9 0.9307 hCV601946 rs524802 hCV26697405 rs547483 0.51 0.9 0.9624 hCV601946 rs524802 hCV26697407 rs496872 0.51 0.9 0.9649 hCV601946 rs524802 hCV27493801 rs3745768 0.51 0.9 0.9307 hCV601946 rs524802 hCV30209952 rs10403679 0.51 0.9 0.9604 hCV601946 rs524802 hCV601938 rs519551 0.51 0.9 0.9649 hCV601946 rs524802 hCV601939 rs565721 0.51 0.9 0.9649 hCV601946 rs524802 hCV601940 rs474017 0.51 0.9 0.9624 hCV601946 rs524802 hCV601941 rs569371 0.51 0.9 0.9604 hCV601946 rs524802 hCV601945 rs528504 0.51 0.9 0.9624 hCV601946 rs524802 hCV601954 rs513406 0.51 0.9 0.9649 hCV601946 rs524802 hCV8712373 rs1667343 0.51 0.9 0.9639 hCV601946 rs524802 hCV8712515 rs826304 0.51 0.9 0.9624 hCV601946 rs524802 hCV8712596 rs826303 0.51 0.9 0.9649 hCV601946 rs524802 hCV8712603 rs826296 0.51 0.9 0.9642 hCV601946 rs524802 hDV70773633 rs16971873 0.51 0.9 0.9649 hCV601961 rs568654 hCV11467027 rs826262 0.51 0.9 1 hCV601961 rs568654 hCV32351622 rs519606 0.51 0.9 0.9649 hCV601961 rs568654 hCV601959 rs540451 0.51 0.9 1 hCV601961 rs568654 hCV601962 rs544543 0.51 0.9 1 hCV601961 rs568654 hCV601964 rs505717 0.51 0.9 1 hCV601961 rs568654 hCV601966 rs551717 0.51 0.9 1 hCV601961 rs568654 hCV601969 rs510757 0.51 0.9 1 hCV601961 rs568654 hCV601972 rs484001 0.51 0.9 1 hCV601961 rs568654 hCV8712620 rs826290 0.51 0.9 1 hCV601961 rs568654 hCV8712646 rs1644711 0.51 0.9 1 hCV601962 rs544543 hCV11467027 rs826262 0.51 0.9 1 hCV601962 rs544543 hCV32351622 rs519606 0.51 0.9 0.9658 hCV601962 rs544543 hCV601959 rs540451 0.51 0.9 1 hCV601962 rs544543 hCV601961 rs568654 0.51 0.9 1 hCV601962 rs544543 hCV601964 rs505717 0.51 0.9 1 hCV601962 rs544543 hCV601966 rs551717 0.51 0.9 1 hCV601962 rs544543 hCV601969 rs510757 0.51 0.9 1 hCV601962 rs544543 hCV601972 rs484001 0.51 0.9 1 hCV601962 rs544543 hCV8712620 rs826290 0.51 0.9 1 hCV601962 rs544543 hCV8712646 rs1644711 0.51 0.9 1 hCV610861 rs636887 hCV8821402 rs1076052 0.51 0.9 1 hCV621313 rs471364 hCV16053903 rs2616751 0.51 0.9 1 hCV621313 rs471364 hCV27926761 rs3933785 0.51 0.9 1 hCV621313 rs471364 hCV27993845 rs3933784 0.51 0.9 1 hCV621313 rs471364 hCV28015592 rs4237138 0.51 0.9 1 hCV621313 rs471364 hCV31935994 rs1475229 0.51 0.9 1 hCV7442005 rs1538584 hCV11759640 rs7850573 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV11759644 rs6560584 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV11759645 rs7034303 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV11759647 rs7048937 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV11760387 rs2309422 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV11760421 rs12056979 0.51 0.495145847 0.6526 hCV7442005 rs1538584 hCV11761216 rs7874888 0.51 0.495145847 0.6359 hCV7442005 rs1538584 hCV11761223 rs2309426 0.51 0.495145847 0.6079 hCV7442005 rs1538584 hCV11761237 rs4329331 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV11761239 rs4338173 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV11761245 rs7043149 0.51 0.495145847 1 hCV7442005 rs1538584 hCV1844076 rs1339546 0.51 0.495145847 0.7161 hCV7442005 rs1538584 hCV20896 rs2309424 0.51 0.495145847 0.7161 hCV7442005 rs1538584 hCV25805877 rs3750549 0.51 0.495145847 0.6376 hCV7442005 rs1538584 hCV26566188 rs4375066 0.51 0.495145847 0.6691 hCV7442005 rs1538584 hCV26566190 rs3927676 0.51 0.495145847 0.6691 hCV7442005 rs1538584 hCV26566432 rs4076288 0.51 0.495145847 0.8185 hCV7442005 rs1538584 hCV26566437 rs4421408 0.51 0.495145847 0.6526 hCV7442005 rs1538584 hCV26566445 rs4339703 0.51 0.495145847 0.8065 hCV7442005 rs1538584 hCV27970553 rs5006364 0.51 0.495145847 0.8065 hCV7442005 rs1538584 hCV27996874 rs4745701 0.51 0.495145847 0.9644 hCV7442005 rs1538584 hCV29169289 rs6560585 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV29577088 rs9314865 0.51 0.495145847 0.7161 hCV7442005 rs1538584 hCV29830130 rs10217168 0.51 0.495145847 0.7161 hCV7442005 rs1538584 hCV30172680 rs10122932 0.51 0.495145847 0.6452 hCV7442005 rs1538584 hCV30532761 rs10125494 0.51 0.495145847 0.6526 hCV7442005 rs1538584 hCV31363642 rs7862404 0.51 0.495145847 0.6403 hCV7442005 rs1538584 hCV31363652 rs10869961 0.51 0.495145847 0.6526 hCV7442005 rs1538584 hCV31363664 rs10869975 0.51 0.495145847 0.6889 hCV7442005 rs1538584 hCV31363697 rs7041781 0.51 0.495145847 0.6376 hCV7442005 rs1538584 hCV31364135 rs10781440 0.51 0.495145847 0.6798 hCV7442005 rs1538584 hCV31364138 rs7865373 0.51 0.495145847 0.6798 hCV7442005 rs1538584 hCV31364140 rs7467352 0.51 0.495145847 0.6455 hCV7442005 rs1538584 hCV31364141 rs11145460 0.51 0.495145847 0.6661 hCV7442005 rs1538584 hCV446682 rs2309427 0.51 0.495145847 0.6359 hCV7442005 rs1538584 hCV450641 rs10781456 0.51 0.495145847 0.6798 hCV7442005 rs1538584 hCV453560 rs10869992 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV453561 rs10869993 0.51 0.495145847 0.6641 hCV7442005 rs1538584 hCV453562 rs10869994 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hCV453563 rs10869997 0.51 0.495145847 0.678 hCV7442005 rs1538584 hCV456556 rs4076287 0.51 0.495145847 0.6673 hCV7442005 rs1538584 hCV463630 rs2486451 0.51 0.495145847 1 hCV7442005 rs1538584 hCV500456 rs10869976 0.51 0.495145847 0.6857 hCV7442005 rs1538584 hCV7441996 rs867346 0.51 0.495145847 0.6831 hCV7442005 rs1538584 hCV7442003 rs884428 0.51 0.495145847 0.6691 hCV7442005 rs1538584 hCV7442004 rs884429 0.51 0.495145847 0.6691 hCV7442005 rs1538584 hCV7482544 rs1416738 0.51 0.495145847 0.6798 hCV7442005 rs1538584 hDV70840481 rs17062237 0.51 0.495145847 0.6742 hCV7442005 rs1538584 hDV71162544 rs1416739 0.51 0.495145847 0.6567 hCV7442005 rs1538584 hDV81101901 rs4745650 0.51 0.495145847 0.6526 hCV7443062 rs897453 hCV7443053 rs1108579 0.51 0.9 0.9298 hCV7480314 rs3851799 hCV16192346 rs2316758 0.51 0.769799979 1 hCV7480314 rs3851799 hCV2592673 rs4968286 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV2592715 rs3851792 0.51 0.769799979 1 hCV7480314 rs3851799 hCV26660327 rs11869840 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV27899058 rs4074249 0.51 0.769799979 0.8511 hCV7480314 rs3851799 hCV29195255 rs8068715 0.51 0.769799979 1 hCV7480314 rs3851799 hCV29195260 rs3851798 0.51 0.769799979 1 hCV7480314 rs3851799 hCV2959464 rs3760377 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV2959466 rs6504622 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV2960484 rs11653838 0.51 0.769799979 0.8511 hCV7480314 rs3851799 hCV30299603 rs9889762 0.51 0.769799979 0.788 hCV7480314 rs3851799 hCV31479403 rs11079750 0.51 0.769799979 0.8526 hCV7480314 rs3851799 hCV341736 rs11653589 0.51 0.769799979 1 hCV7480314 rs3851799 hCV348972 rs11079747 0.51 0.769799979 0.9616 hCV7480314 rs3851799 hCV473201 rs12950699 0.51 0.769799979 0.8598 hCV7480314 rs3851799 hCV498633 rs4968304 0.51 0.769799979 0.8598 hCV7480314 rs3851799 hCV9268384 rs7216950 0.51 0.769799979 0.8496 hCV7490135 rs1805082 hCV12087046 rs1808579 0.51 0.9 0.9437 hCV7490135 rs1805082 hCV16017395 rs2435307 0.51 0.9 0.9439 hCV7490135 rs1805082 hCV16023276 rs2510340 0.51 0.9 0.931 hCV7490135 rs1805082 hCV25620752 rs7239575 0.51 0.9 1 hCV7490135 rs1805082 hCV27004508 rs2960578 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV2950793 rs1652343 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV29636546 rs1652344 0.51 0.9 1 hCV7490135 rs1805082 hCV3203990 rs1429935 0.51 0.9 0.9624 hCV7490135 rs1805082 hCV3203995 rs1367083 0.51 0.9 0.9623 hCV7490135 rs1805082 hCV3203996 rs6507708 0.51 0.9 0.931 hCV7490135 rs1805082 hCV3204000 rs891387 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV3204001 rs891386 0.51 0.9 0.9271 hCV7490135 rs1805082 hCV3204007 rs2510344 0.51 0.9 1 hCV7490135 rs1805082 hCV3204010 rs6507716 0.51 0.9 0.9812 hCV7490135 rs1805082 hCV3204011 rs12964689 0.51 0.9 1 hCV7490135 rs1805082 hCV3204012 rs4800162 0.51 0.9 1 hCV7490135 rs1805082 hCV3204013 rs4800488 0.51 0.9 1 hCV7490135 rs1805082 hCV3204015 rs6507720 0.51 0.9 1 hCV7490135 rs1805082 hCV3204021 rs11663558 0.51 0.9 0.9271 hCV7490135 rs1805082 hCV3204027 rs1623060 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV3204029 rs1652348 0.51 0.9 1 hCV7490135 rs1805082 hCV3204038 rs1788783 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV7490108 rs1631685 0.51 0.9 0.9628 hCV7490135 rs1805082 hCV7490208 rs1788817 0.51 0.9 0.9436 hCV7490135 rs1805082 hDV77046157 rs4800493 0.51 0.9 0.931 hCV7501549 rs1467412 hCV16230554 rs2426320 0.51 0.9 1 hCV7501549 rs1467412 hCV16230588 rs2426329 0.51 0.9 1 hCV7501549 rs1467412 hCV25618186 rs1467413 0.51 0.9 1 hCV7501549 rs1467412 hCV3120998 rs2253381 0.51 0.9 1 hCV7501549 rs1467412 hCV3120999 rs2426318 0.51 0.9 1 hCV7501549 rs1467412 hCV3121000 rs2426319 0.51 0.9 1 hCV7501549 rs1467412 hCV3121001 rs2426321 0.51 0.9 1 hCV7501549 rs1467412 hCV3121002 rs2426322 0.51 0.9 1 hCV7514870 rs1041981 hCV2451911 rs909253 0.51 0.9 1 hCV7514870 rs1041981 hCV26778971 rs2071591 0.51 0.9 0.9791 hCV7514870 rs1041981 hCV27463589 rs3130059 0.51 0.9 0.9621 hCV7514870 rs1041981 hCV30139067 rs3093974 0.51 0.9 0.958 hCV7514870 rs1041981 hCV3273586 rs2071592 0.51 0.9 0.9234 hCV7514870 rs1041981 hCV3273591 rs2071594 0.51 0.9 0.9791 hCV7514870 rs1041981 hCV3273597 rs2239527 0.51 0.9 0.96 hCV7514870 rs1041981 hCV3273612 rs11796 0.51 0.9 0.9791 hCV7514879 rs1800629 hCV26778874 rs2516482 0.51 0.9 1 hCV7514879 rs1800629 hCV30319025 rs3093988 0.51 0.9 0.9366 hCV7537517 rs1501908 hCV1454065 rs12657266 0.51 0.9 1 hCV7537517 rs1501908 hCV1454067 rs6874202 0.51 0.9 1 hCV7537517 rs1501908 hCV27868704 rs4704727 0.51 0.9 1 hCV7537517 rs1501908 hCV29133696 rs7724832 0.51 0.9 1 hCV7537517 rs1501908 hCV31236212 rs6878680 0.51 0.9 1 hCV7537517 rs1501908 hCV3164263 rs1363232 0.51 0.9 1 hCV7577801 rs11876 hDV75439516 rs3211994 0.51 0.9 1 hCV7618856 rs1143675 hCV1711157 rs1196184 0.51 0.9 1 hCV783138 rs6046 hCV11926372 rs6041 0.51 0.9 0.9575 hCV783138 rs6046 hCV3046089 rs6042 0.51 0.9 0.9165 hCV783138 rs6046 hCV31891145 rs3093253 0.51 0.9 0.9576 hCV783138 rs6046 hCV50000100 rs561241 0.51 0.9 0.9234 hCV783138 rs6046 hCV783148 rs491098 0.51 0.9 0.9165 hCV7900503 rs3732379 hCV246550 rs11713282 0.51 0.9 1 hCV7900503 rs3732379 hCV246551 rs11129819 0.51 0.9 1 hCV7900503 rs3732379 hCV403264 rs11711391 0.51 0.9 1 hCV7900503 rs3732379 hCV7900501 rs11709600 0.51 0.9 1 hCV7900503 rs3732379 hCV7900502 rs11710546 0.51 0.9 1 hCV7900503 rs3732379 hCV8759805 rs1050592 0.51 0.9 1 hCV7910239 rs1541296 hCV3044407 rs2003149 0.51 0.9 1 hCV7910239 rs1541296 hCV3044408 rs1809319 0.51 0.9 1 hCV795441 rs401502 hCV795442 rs375947 0.51 0.9 1 hCV795441 rs401502 hCV795446 rs365179 0.51 0.9 0.9581 hCV795441 rs401502 hCV795454 rs429774 0.51 0.9 1 hCV795441 rs401502 hCV795455 rs382634 0.51 0.9 0.9103 hCV795441 rs401502 hCV795459 rs376008 0.51 0.9 1 hCV795441 rs401502 hDV71612301 rs17852635 0.51 0.9 1 hCV795442 rs375947 hCV795441 rs401502 0.51 0.9 1 hCV795442 rs375947 hCV795446 rs365179 0.51 0.9 0.9552 hCV795442 rs375947 hCV795454 rs429774 0.51 0.9 0.9795 hCV795442 rs375947 hCV795455 rs382634 0.51 0.9 0.9059 hCV795442 rs375947 hCV795459 rs376008 0.51 0.9 1 hCV795442 rs375947 hDV71612301 rs17852635 0.51 0.9 0.9795 hCV818008 rs5918 hCV29197695 rs7214096 0.51 0.9 1 hCV818008 rs5918 hCV29197704 rs8069732 0.51 0.9 1 hCV8369472 rs1447351 hCV11323166 rs7121092 0.51 0.9 1 hCV8369472 rs1447351 hCV26158785 rs4406791 0.51 0.9 0.9649 hCV8369472 rs1447351 hCV26158787 rs4753073 0.51 0.9 1 hCV8369472 rs1447351 hCV27965689 rs4753072 0.51 0.9 1 hCV8369472 rs1447351 hCV29662341 rs6483213 0.51 0.9 0.9643 hCV8369472 rs1447351 hCV3256840 rs9666752 0.51 0.9 0.9649 hCV8369472 rs1447351 hCV3256848 rs1447352 0.51 0.9 1 hCV8369472 rs1447351 hCV3256849 rs1597023 0.51 0.9 0.963 hCV8369472 rs1447351 hCV3256853 rs4611171 0.51 0.9 0.963 hCV8369472 rs1447351 hCV8369473 rs1447350 0.51 0.9 1 hCV8369472 rs1447351 hCV8369474 rs1562444 0.51 0.9 0.9813 hCV8379452 rs4908781 hCV11675982 rs1953827 0.51 0.494607042 0.4974 hCV8379452 rs4908781 hCV11675985 rs12136766 0.51 0.494607042 0.4974 hCV8379452 rs4908781 hCV1188706 rs2185205 0.51 0.494607042 0.8302 hCV8379452 rs4908781 hCV1188726 rs6698830 0.51 0.494607042 0.7147 hCV8379452 rs4908781 hCV1188747 rs4908511 0.51 0.494607042 0.7134 hCV8379452 rs4908781 hCV1188748 rs12028160 0.51 0.494607042 0.7134 hCV8379452 rs4908781 hCV1265858 rs11121194 0.51 0.494607042 0.4974 hCV8379452 rs4908781 hCV27157851 rs4480384 0.51 0.494607042 0.5249 hCV8379452 rs4908781 hCV29368911 rs6577513 0.51 0.494607042 0.5458 hCV8379452 rs4908781 hCV29855298 rs6690928 0.51 0.494607042 0.7355 hCV8379452 rs4908781 hCV29981708 rs7554486 0.51 0.494607042 0.5371 hCV8379452 rs4908781 hCV30233466 rs7513880 0.51 0.494607042 0.7147 hCV8379452 rs4908781 hCV30413939 rs6701331 0.51 0.494607042 0.4974 hCV8379452 rs4908781 hCV30413946 rs7537982 0.51 0.494607042 0.5249 hCV8379452 rs4908781 hCV3086941 rs7556169 0.51 0.494607042 0.526 hCV8379452 rs4908781 hCV3086945 rs6695867 0.51 0.494607042 0.5543 hCV8379452 rs4908781 hCV3086948 rs10864361 0.51 0.494607042 0.5552 hCV8379452 rs4908781 hCV3086949 rs11121212 0.51 0.494607042 0.5342 hCV8379452 rs4908781 hCV3086954 rs1463053 0.51 0.494607042 0.526 hCV8379452 rs4908781 hCV3086956 rs1463052 0.51 0.494607042 0.4974 hCV8379452 rs4908781 hCV3086959 rs7520025 0.51 0.494607042 0.5204 hCV8379452 rs4908781 hCV3086974 rs1318218 0.51 0.494607042 0.5323 hCV8379452 rs4908781 hCV3086976 rs11121204 0.51 0.494607042 0.5249 hCV8379452 rs4908781 hCV32055489 rs10864360 0.51 0.494607042 0.5342 hCV8379452 rs4908781 hCV32055498 rs4908507 0.51 0.494607042 0.5543 hCV8379452 rs4908781 hCV32055554 rs12024032 0.51 0.494607042 0.7134 hCV8379452 rs4908781 hCV32055587 rs10864367 0.51 0.494607042 0.7147 hCV8379452 rs4908781 hCV32055630 rs4908518 0.51 0.494607042 0.8302 hCV8379452 rs4908781 hCV32392515 rs4908505 0.51 0.494607042 0.5552 hCV8379452 rs4908781 hDV75072264 rs12403640 0.51 0.494607042 0.6803 hCV8379452 rs4908781 hDV77058075 rs4908506 0.51 0.494607042 0.526 hCV8420416 rs719909 hCV29251974 rs7905163 0.51 0.9 1 hCV8420416 rs719909 hCV31659989 rs11185804 0.51 0.9 1 hCV8420416 rs719909 hCV31659993 rs11185799 0.51 0.9 1 hCV8420416 rs719909 hCV31659999 rs11185793 0.51 0.9 1 hCV8420416 rs719909 hCV31660000 rs11185792 0.51 0.9 1 hCV8420416 rs719909 hCV31660001 rs11185791 0.51 0.9 1 hCV8420416 rs719909 hCV31660002 rs10881610 0.51 0.9 1 hCV8420416 rs719909 hCV31660004 rs10881608 0.51 0.9 1 hCV8420416 rs719909 hCV31660007 rs11185790 0.51 0.9 1 hCV8420416 rs719909 hCV31660048 rs12777243 0.51 0.9 1 hCV8420416 rs719909 hCV8420325 rs11185780 0.51 0.9 1 hCV8420416 rs719909 hCV8420398 rs11185773 0.51 0.9 1 hCV8420416 rs719909 hCV8870224 rs1075374 0.51 0.9 1 hCV8708473 rs1800469 hCV11464030 rs1982072 0.51 0.9 1 hCV8708473 rs1800469 hCV15873885 rs2241714 0.51 0.9 0.9776 hCV8708473 rs1800469 hCV15873886 rs2241715 0.51 0.9 0.9774 hCV8708473 rs1800469 hCV16193065 rs2317130 0.51 0.9 1 hCV8709053 rs4880 hCV1362043 rs2842960 0.51 0.9 1 hCV8709053 rs4880 hCV1362077 rs2842991 0.51 0.9 0.9625 hCV8709053 rs4880 hCV1362081 rs2758319 0.51 0.9 0.9293 hCV8709053 rs4880 hCV16072287 rs2855116 0.51 0.9 0.9625 hCV8709053 rs4880 hCV16288770 rs2758331 0.51 0.9 0.9625 hCV8709053 rs4880 hCV27040091 rs2842989 0.51 0.9 0.9625 hCV8709053 rs4880 hCV8709029 rs8031 0.51 0.9 0.9625 hCV8718197 rs1050998 hCV15885167 rs2277680 0.51 0.9 1 hCV8718197 rs1050998 hCV31086637 rs8071612 0.51 0.9 1 hCV8718197 rs1050998 hCV31086638 rs8073062 0.51 0.9 1 hCV8726337 rs5498 hCV16044655 rs2075741 0.51 0.9 0.9256 hCV8726337 rs5498 hCV1844464 rs885743 0.51 0.9 0.9604 hCV8726337 rs5498 hCV27478391 rs3093030 0.51 0.9 0.9217 hCV8726337 rs5498 hCV31765037 rs12150978 0.51 0.9 0.9221 hCV8737990 rs419598 hCV11948077 rs16065 0.51 0.9 0.9557 hCV8737990 rs419598 hCV11948080 rs451578 0.51 0.9 1 hCV8737990 rs419598 hCV11948081 rs432014 0.51 0.9 1 hCV8737990 rs419598 hCV3133511 rs4251984 0.51 0.9 0.9557 hCV8737990 rs419598 hCV3133512 rs4251985 0.51 0.9 0.9557 hCV8737990 rs419598 hCV3133519 rs2853628 0.51 0.9 0.9432 hCV8737990 rs419598 hCV32060324 rs4251967 0.51 0.9 1 hCV8737990 rs419598 hCV3252471 rs444413 0.51 0.9 1 hCV8737990 rs419598 hCV3252474 rs1794067 0.51 0.9 1 hCV8737990 rs419598 hCV3252475 rs1794068 0.51 0.9 1 hCV8737990 rs419598 hCV8737960 rs440286 0.51 0.9 0.9537 hCV8737990 rs419598 hCV8737965 rs431726 0.51 0.9 0.9547 hCV8737990 rs419598 hCV8737970 rs454078 0.51 0.9 1 hCV8737990 rs419598 hCV8737973 rs128964 0.51 0.9 1 hCV8737990 rs419598 hCV8737974 rs447713 0.51 0.9 1 hCV8737990 rs419598 hCV8737978 rs408392 0.51 0.9 1 hCV8737990 rs419598 hCV8737979 rs442710 0.51 0.9 1 hCV8737990 rs419598 hCV8737980 rs495410 0.51 0.9 1 hCV8737990 rs419598 hCV8737984 rs495282 0.51 0.9 1 hCV8737990 rs419598 hCV8737985 rs446433 0.51 0.9 1 hCV8737990 rs419598 hCV8737986 rs423904 0.51 0.9 1 hCV8737990 rs419598 hCV948686 rs315936 0.51 0.9 1 hCV8737990 rs419598 hDV76981932 rs4251970 0.51 0.9 0.9556 hCV8784787 rs688976 hCV12020218 rs613423 0.51 0.9 1 hCV8784787 rs688976 hCV12020219 rs624601 0.51 0.9 1 hCV8784787 rs688976 hCV16163350 rs2073825 0.51 0.9 1 hCV8784787 rs688976 hCV25610774 rs8176748 0.51 0.9 1 hCV8784787 rs688976 hCV25610819 rs8176740 0.51 0.9 1 hCV8784787 rs688976 hCV25610830 rs8176717 0.51 0.9 1 hCV8784787 rs688976 hCV25610847 rs8176714 0.51 0.9 1 hCV8784787 rs688976 hCV26744836 rs500428 0.51 0.9 0.9766 hCV8784787 rs688976 hCV26744838 rs502361 0.51 0.9 1 hCV8784787 rs688976 hCV29669589 rs8176732 0.51 0.9 1 hCV8784787 rs688976 hCV30120679 rs8176728 0.51 0.9 1 hCV8784787 rs688976 hCV30192755 rs568203 0.51 0.9 1 hCV8784787 rs688976 hCV30534973 rs626035 0.51 0.9 1 hCV8784787 rs688976 hCV30661132 rs11244053 0.51 0.9 1 hCV8784787 rs688976 hCV3183108 rs474279 0.51 0.9 1 hCV8784787 rs688976 hCV3183120 rs574311 0.51 0.9 1 hCV8784787 rs688976 hCV8784788 rs493211 0.51 0.9 0.9497 hCV8784787 rs688976 hCV997885 rs641959 0.51 0.9 0.9129 hCV8784787 rs688976 hCV997886 rs641943 0.51 0.9 0.9541 hCV8784787 rs688976 hCV997887 rs514708 0.51 0.9 0.9541 hCV8784787 rs688976 hCV997888 rs517414 0.51 0.9 1 hCV8784787 rs688976 hCV997889 rs638756 0.51 0.9 0.9503 hCV8784787 rs688976 hCV997893 rs547643 0.51 0.9 1 hCV8784787 rs688976 hCV997897 rs549446 0.51 0.9 1 hCV8784787 rs688976 hCV997902 rs574347 0.51 0.9 1 hCV8784787 rs688976 hCV997904 rs579483 0.51 0.9 1 hCV8784787 rs688976 hCV997905 rs579622 0.51 0.9 1 hCV8784787 rs688976 hCV997906 rs672316 0.51 0.9 0.9541 hCV8784787 rs688976 hCV997925 rs552148 0.51 0.9 0.9767 hCV8784787 rs688976 hDV77084283 rs549331 0.51 0.9 1 hCV8784787 rs688976 hDV81175228 rs625593 0.51 0.9 1 hCV8785824 rs1412426 hCV11841945 rs10815370 0.51 0.9 0.93 hCV8785824 rs1412426 hCV12096524 rs1929996 0.51 0.9 1 hCV8785824 rs1412426 hCV2762174 rs4742167 0.51 0.9 0.93 hCV8785824 rs1412426 hCV31940475 rs4742166 0.51 0.9 1 hCV8785824 rs1412426 hCV8785825 rs1412425 0.51 0.9 1 hCV8785827 rs992969 hCV12096527 rs1888909 0.51 0.9 0.9767 hCV8785827 rs992969 hCV12096531 rs928413 0.51 0.9 0.9767 hCV8785827 rs992969 hCV16108911 rs2095044 0.51 0.9 0.9616 hCV8785827 rs992969 hCV16225421 rs2381416 0.51 0.9 0.9252 hCV8785827 rs992969 hCV2762168 rs3939286 0.51 0.9 1 hCV8785827 rs992969 hCV31940459 rs7848215 0.51 0.9 0.9252 hCV8804621 rs1390938 hCV16135403 rs2132699 0.51 0.9 1 hCV8804621 rs1390938 hCV2716010 rs6586898 0.51 0.9 0.9759 hCV8804621 rs1390938 hCV27964220 rs4921694 0.51 0.9 1 hCV8804621 rs1390938 hCV29049483 rs6992927 0.51 0.9 1 hCV8804621 rs1390938 hCV30973375 rs7006986 0.51 0.9 1 hCV8804621 rs1390938 hCV8804610 rs952859 0.51 0.9 1 hCV8804621 rs1390938 hCV8804615 rs952858 0.51 0.9 1 hCV8804621 rs1390938 hCV8804626 rs988713 0.51 0.9 0.9756 hCV8823713 rs1472228 hCV1188731 rs4908514 0.51 0.900026297 1 hCV8823713 rs1472228 hCV1188735 rs10864366 0.51 0.900026297 1 hCV8823713 rs1472228 hCV27157507 rs6664000 0.51 0.900026297 1 hCV8823713 rs1472228 hCV27157524 rs6577531 0.51 0.900026297 0.9314 hCV8823713 rs1472228 hCV27884601 rs4908776 0.51 0.900026297 1 hCV8823713 rs1472228 hCV28023091 rs4908773 0.51 0.900026297 1 hCV8823713 rs1472228 hCV29368919 rs4908513 0.51 0.900026297 1 hCV8823713 rs1472228 hCV29873524 rs7533113 0.51 0.900026297 1 hCV8823713 rs1472228 hCV29945430 rs7517436 0.51 0.900026297 1 hCV8823713 rs1472228 hCV30035535 rs7518204 0.51 0.900026297 1 hCV8823713 rs1472228 hCV32055527 rs10864364 0.51 0.900026297 1 hCV8823713 rs1472228 hCV32055579 rs6577522 0.51 0.900026297 1 hCV8823713 rs1472228 hCV32055595 rs6577524 0.51 0.900026297 1 hCV8823713 rs1472228 hCV32055596 rs6577525 0.51 0.900026297 1 hCV8824248 rs1543711 hCV1188659 rs3820037 0.51 0.867554387 1 hCV8824248 rs1543711 hCV1188660 rs6660137 0.51 0.867554387 1 hCV8824248 rs1543711 hCV1188664 rs2765511 0.51 0.867554387 1 hCV8824248 rs1543711 hCV1188665 rs2781060 0.51 0.867554387 1 hCV8824248 rs1543711 hCV1188676 rs11121247 0.51 0.867554387 1 hCV8824248 rs1543711 hCV12040675 rs2038904 0.51 0.867554387 1 hCV8824248 rs1543711 hCV15932991 rs2781067 0.51 0.867554387 1 hCV8824248 rs1543711 hCV15932992 rs2781068 0.51 0.867554387 1 hCV8824248 rs1543711 hCV27157546 rs11811795 0.51 0.867554387 0.942 hCV8824248 rs1543711 hCV8824241 rs1325920 0.51 0.867554387 0.9416 hCV8824248 rs1543711 hCV8824244 rs1006950 0.51 0.867554387 1 hCV8824394 rs1443929 hCV15882429 rs2289732 0.51 0.868495377 1 hCV8824394 rs1443929 hCV2741759 rs11121179 0.51 0.868495377 1 hCV8824394 rs1443929 hCV27474399 rs3753275 0.51 0.868495377 0.8913 hCV8824394 rs1443929 hCV2943451 rs902355 0.51 0.868495377 0.9232 hCV8824394 rs1443929 hCV2943853 rs301793 0.51 0.868495377 1 hCV8824394 rs1443929 hCV2966436 rs11121174 0.51 0.868495377 1 hCV8824394 rs1443929 hCV2966437 rs11580417 0.51 0.868495377 1 hCV8824394 rs1443929 hCV2966441 rs6684863 0.51 0.868495377 1 hCV8824394 rs1443929 hCV2966444 rs11121171 0.51 0.868495377 0.9345 hCV8824394 rs1443929 hCV32055284 rs12079653 0.51 0.868495377 0.9336 hCV8824394 rs1443929 hCV529182 rs301800 0.51 0.868495377 0.9634 hCV8824394 rs1443929 hCV877241 rs301788 0.51 0.868495377 1 hCV8824394 rs1443929 hCV8824424 rs1058790 0.51 0.868495377 0.9345 hCV8824394 rs1443929 hCV8824425 rs1058791 0.51 0.868495377 0.8913 hCV8824424 rs1058790 hCV15882429 rs2289732 0.51 0.899566528 0.9381 hCV8824424 rs1058790 hCV2741759 rs11121179 0.51 0.899566528 0.9345 hCV8824424 rs1058790 hCV2943451 rs902355 0.51 0.899566528 0.928 hCV8824424 rs1058790 hCV2943853 rs301793 0.51 0.899566528 0.9381 hCV8824424 rs1058790 hCV2966436 rs11121174 0.51 0.899566528 0.9381 hCV8824424 rs1058790 hCV2966437 rs11580417 0.51 0.899566528 0.9381 hCV8824424 rs1058790 hCV2966441 rs6684863 0.51 0.899566528 0.9381 hCV8824424 rs1058790 hCV2966444 rs11121171 0.51 0.899566528 1 hCV8824424 rs1058790 hCV877241 rs301788 0.51 0.899566528 0.9345 hCV8824424 rs1058790 hCV8824394 rs1443929 0.51 0.899566528 0.9345 hCV8824424 rs1058790 hCV8824425 rs1058791 0.51 0.899566528 1 hCV8824425 rs1058791 hCV15882429 rs2289732 0.51 0.90786153 0.9345 hCV8824425 rs1058791 hCV2943451 rs902355 0.51 0.90786153 0.9232 hCV8824425 rs1058791 hCV2943853 rs301793 0.51 0.90786153 0.9345 hCV8824425 rs1058791 hCV2966436 rs11121174 0.51 0.90786153 0.9345 hCV8824425 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hCV8892418 rs901746 hCV27484275 rs3781622 0.51 0.9 0.907 hCV8892418 rs901746 hCV30887885 rs11039166 0.51 0.9 0.907 hCV8892418 rs901746 hCV30887894 rs4752824 0.51 0.9 0.9359 hCV8892418 rs901746 hCV607862 rs326214 0.51 0.9 0.9566 hCV8892418 rs901746 hCV8890616 rs1052373 0.51 0.9 0.9566 hCV8892418 rs901746 hCV8892417 rs2013867 0.51 0.9 1 hCV8892418 rs901746 hCV8892456 rs1449627 0.51 0.9 0.9566 hCV8892418 rs901746 hCV8892463 rs3847502 0.51 0.9 0.9157 hCV8895373 rs1503185 hCV11665699 rs11039528 0.51 0.9 1 hCV8895373 rs1503185 hCV11665715 rs11039522 0.51 0.9 0.9186 hCV8895373 rs1503185 hCV11665751 rs12576134 0.51 0.9 0.9133 hCV8895373 rs1503185 hCV142450 rs11607114 0.51 0.9 1 hCV8895373 rs1503185 hCV288149 rs1566734 0.51 0.9 0.9564 hCV8895373 rs1503185 hCV31699609 rs12577284 0.51 0.9 0.9563 hCV8895373 rs1503185 hCV31699653 rs11599936 0.51 0.9 0.9236 hCV8895373 rs1503185 hCV440189 rs11600061 0.51 0.9 0.9278 hCV8895373 rs1503185 hCV8895366 rs905476 0.51 0.9 0.9564 hCV8901525 rs861539 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hCV9506149 rs1250259 hCV2110751 rs1250229 0.51 0.9 0.9111 hCV9506149 rs1250259 hCV8838302 rs1250241 0.51 0.9 0.955 hCV9506149 rs1250259 hCV8838303 rs1250240 0.51 0.9 0.955 hCV9506149 rs1250259 hCV9506150 rs1250242 0.51 0.9 0.955 hCV9581635 rs1748195 hCV11864156 rs10889334 0.51 0.9 0.9583 hCV9581635 rs1748195 hCV11864162 rs1167998 0.51 0.9 0.9791 hCV9581635 rs1748195 hCV11865171 rs11208004 0.51 0.9 0.979 hCV9581635 rs1748195 hCV11865185 rs10789117 0.51 0.9 1 hCV9581635 rs1748195 hCV11865196 rs7555577 0.51 0.9 0.919 hCV9581635 rs1748195 hCV11865201 rs10159255 0.51 0.9 0.958 hCV9581635 rs1748195 hCV12103105 rs1184865 0.51 0.9 0.9791 hCV9581635 rs1748195 hCV12103127 rs1979722 0.51 0.9 0.9578 hCV9581635 rs1748195 hCV12103499 rs2029763 0.51 0.9 0.9558 hCV9581635 rs1748195 hCV12103502 rs1168023 0.51 0.9 1 hCV9581635 rs1748195 hCV1236535 rs1168042 0.51 0.9 1 hCV9581635 rs1748195 hCV149783 rs1168045 0.51 0.9 1 hCV9581635 rs1748195 hCV16214290 rs2366638 0.51 0.9 1 hCV9581635 rs1748195 hCV1778957 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hCV31145291 rs11207995 0.51 0.9 0.9789 hCV9588862 rs995000 hCV31145298 rs11207992 0.51 0.9 1 hCV9588862 rs995000 hCV31145302 rs12116574 0.51 0.9 1 hCV9588862 rs995000 hCV31145332 rs11207981 0.51 0.9 0.9538 hCV9588862 rs995000 hCV3122390 rs1748200 0.51 0.9 0.959 hCV9588862 rs995000 hCV316299 rs1168026 0.51 0.9 0.959 hCV9588862 rs995000 hCV316303 rs1168031 0.51 0.9 0.9586 hCV9588862 rs995000 hCV32220452 rs12090886 0.51 0.9 1 hCV9588862 rs995000 hCV32220453 rs10889337 0.51 0.9 0.9585 hCV9588862 rs995000 hCV32220467 rs10889333 0.51 0.9 1 hCV9588862 rs995000 hCV32220469 rs10889332 0.51 0.9 0.979 hCV9588862 rs995000 hCV32220470 rs11207974 0.51 0.9 0.959 hCV9588862 rs995000 hCV32220491 rs11577840 0.51 0.9 0.9586 hCV9588862 rs995000 hCV32220495 rs11207969 0.51 0.9 0.979 hCV9588862 rs995000 hCV408090 rs1183260 0.51 0.9 0.9566 hCV9588862 rs995000 hCV445207 rs1627591 0.51 0.9 0.959 hCV9588862 rs995000 hCV71419 rs2131925 0.51 0.9 0.959 hCV9588862 rs995000 hCV857102 rs624660 0.51 0.9 0.979 hCV9588862 rs995000 hCV857103 rs636497 0.51 0.9 0.9577 hCV9588862 rs995000 hCV857104 rs636523 0.51 0.9 1 hCV9588862 rs995000 hCV857108 rs597078 0.51 0.9 0.958 hCV9588862 rs995000 hCV857109 rs597470 0.51 0.9 0.959 hCV9588862 rs995000 hCV857110 rs583609 0.51 0.9 0.979 hCV9588862 rs995000 hCV857121 rs642845 0.51 0.9 0.958 hCV9588862 rs995000 hCV857122 rs656297 0.51 0.9 0.979 hCV9588862 rs995000 hCV857123 rs638305 0.51 0.9 0.959 hCV9588862 rs995000 hCV857127 rs631106 0.51 0.9 0.9577 hCV9588862 rs995000 hCV9508668 rs1781195 0.51 0.9 0.979 hCV9588862 rs995000 hCV9581062 rs998403 0.51 0.9 1 hCV9588862 rs995000 hCV9581570 rs1168036 0.51 0.9 1 hCV9588862 rs995000 hCV9581571 rs1002687 0.51 0.9 0.959 hCV9588862 rs995000 hCV9581580 rs1168032 0.51 0.9 0.958 hCV9588862 rs995000 hCV9581581 rs1168030 0.51 0.9 0.959 hCV9588862 rs995000 hCV9581590 rs1168018 0.51 0.9 0.9789 hCV9588862 rs995000 hCV9581606 rs1168022 0.51 0.9 0.9558 hCV9588862 rs995000 hCV9581615 rs1748201 0.51 0.9 0.9789 hCV9588862 rs995000 hCV9581635 rs1748195 0.51 0.9 0.979 hCV9588862 rs995000 hCV9581636 rs3850634 0.51 0.9 1 hCV9588862 rs995000 hCV9581680 rs1748197 0.51 0.9 0.959 hCV9588862 rs995000 hCV9581691 rs1570694 0.51 0.9 1 hCV9588862 rs995000 hCV9583244 rs783291 0.51 0.9 0.959 hCV9588862 rs995000 hCV9588770 rs1007205 0.51 0.9 0.959 hCV9588862 rs995000 hCV9588793 rs1168009 0.51 0.9 0.9365 hCV9588862 rs995000 hCV9588794 rs1168010 0.51 0.9 0.936 hCV9588862 rs995000 hCV9588829 rs1781212 0.51 0.9 0.959 hCV9588862 rs995000 hCV9588850 rs1168013 0.51 0.9 0.979 hCV9588862 rs995000 hCV9588875 rs1168086 0.51 0.9 0.9551 hCV9588862 rs995000 hCV9588886 rs1168089 0.51 0.9 0.979 hCV9588862 rs995000 hCV9588930 rs1168099 0.51 0.9 0.979 hCV9588862 rs995000 hCV9588985 rs1168124 0.51 0.9 0.959 hCV9588862 rs995000 hDV75176134 rs1781221 0.51 0.9 0.959 hCV9596963 rs6115 hCV9596972 rs6112 0.51 0.9 0.9634 hCV9604851 rs1805002 hDV77041261 rs4758402 0.51 0.9 1 hDV70661573 rs16875009 hCV2928259 rs6867948 0.51 0.409905558 0.656 hDV70661573 rs16875009 hCV2928266 rs11742566 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928267 rs12517136 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928268 rs11134096 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928269 rs11134097 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928270 rs12515050 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928271 rs12520783 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928278 rs12522919 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928283 rs12518805 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928284 rs12518833 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928288 rs11748003 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928289 rs7446660 0.51 0.409905558 0.4246 hDV70661573 rs16875009 hCV2928293 rs12517784 0.51 0.409905558 1 hDV70661573 rs16875009 hCV2928295 rs1428025 0.51 0.409905558 0.4246 hDV70661573 rs16875009 hCV2928306 rs1428024 0.51 0.409905558 1 hDV70661573 rs16875009 hCV32226945 rs12521996 0.51 0.409905558 1 hDV70661573 rs16875009 hCV32226946 rs12517751 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703783 rs16874942 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703799 rs16874970 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703820 rs16874994 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703822 rs16874998 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703832 rs16875012 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703845 rs16875031 0.51 0.409905558 0.8803 hDV70661573 rs16875009 hDV70703846 rs16875033 0.51 0.409905558 1 hDV70661573 rs16875009 hDV70703851 rs16875038 0.51 0.409905558 1 hDV70938014 rs17321515 hCV11593303 rs2980871 0.51 0.9 0.9634 hDV70938014 rs17321515 hCV12004940 rs2001844 0.51 0.9 1 hDV70938014 rs17321515 hCV15883779 rs2980869 0.51 0.9 1 hDV70938014 rs17321515 hCV15883790 rs2980875 0.51 0.9 0.9619 hDV70938014 rs17321515 hCV15954624 rs2954022 0.51 0.9 0.9634 hDV70938014 rs17321515 hCV15954645 rs2954029 0.51 0.9 0.9634 hDV70938014 rs17321515 hCV26372062 rs2980856 0.51 0.9 1 hDV70938014 rs17321515 hCV26372064 rs2980855 0.51 0.9 1 hDV70938014 rs17321515 hCV26372065 rs2980854 0.51 0.9 1 hDV70938014 rs17321515 hCV26372066 rs2980853 0.51 0.9 1 hDV70938014 rs17321515 hCV26372069 rs2980882 0.51 0.9 1 hDV70938014 rs17321515 hCV29719123 rs6982636 0.51 0.9 1 hDV70938014 rs17321515 hCV309481 rs2954019 0.51 0.9 1 hDV70938014 rs17321515 hCV469160 rs2954031 0.51 0.9 0.9279 hDV70938014 rs17321515 hCV85515 rs10808546 0.51 0.9 0.9064 hDV70973697 rs17593921 hDV70715540 rs16891266 0.51 0.612665933 0.6234 hDV70977122 rs17616652 hCV11627552 rs2316667 0.51 0.442542981 0.7059 hDV70977122 rs17616652 hCV1718966 rs4968305 0.51 0.442542981 0.7074 hDV70977122 rs17616652 hCV26683367 rs9894300 0.51 0.442542981 0.6395 hDV70977122 rs17616652 hCV26683368 rs2004580 0.51 0.442542981 0.6405 hDV70977122 rs17616652 hCV29195269 rs7221042 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hCV30515746 rs10491149 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hCV31479223 rs11570460 0.51 0.442542981 0.7356 hDV70977122 rs17616652 hCV31479380 rs4520895 0.51 0.442542981 0.642 hDV70977122 rs17616652 hCV7451110 rs1515754 0.51 0.442542981 0.7356 hDV70977122 rs17616652 hCV9268649 rs16941168 0.51 0.442542981 0.5852 hDV70977122 rs17616652 hDV70590478 rs9897338 0.51 0.442542981 0.642 hDV70977122 rs17616652 hDV70751669 rs16941353 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hDV70751822 rs16941584 0.51 0.442542981 0.7366 hDV70977122 rs17616652 hDV70975179 rs17603901 0.51 0.442542981 0.6562 hDV70977122 rs17616652 hDV70987720 rs17676978 0.51 0.442542981 0.7843 hDV70977122 rs17616652 hDV75285090 rs2667804 0.51 0.442542981 0.7074

TABLE 7 Association test results from two MI case-control studies Gene Risk CCF UCSF SNP Symbol Allele OR (95% CI) P Strata Model OR (95% CI) P Strata Model Tested* rs6668968 AQP10 A 1.29 (1.07-1.57) 0.008 ALL add 1.16 (1.00-1.35) 0.050 ALL add † rs13078881 BTD G 2.95 (1.27-6.89) 0.012 F add 1.73 (0.94-3.20) 0.079 F add † rs1051038 COG2 A 1.23 (0.99-1.53) 0.063 ALL add 1.19 (0.97-1.46) 0.088 ALL rec † rs2035029 DCC G 1.35 (1.04-1.76) 0.024 ALL dom 1.22 (1.00-1.50) 0.053 ALL dom † Chr17: 74022684 DNAHL1 C 1.85 (0.95-3.63) 0.072 ALL add 1.96 (0.97-3.94) 0.060 M add † rs34639489 ERV3 C 1.16 (0.98-1.38) 0.092 ALL add 1.13 (0.98-1.30) 0.086 ALL add † rs4149965 EXO1 A 1.34 (1.03-1.73) 0.028 M add 1.38 (1.10-1.73) 0.005 M add † rs2304024 FAT2 G 1.20 (0.97-1.50) 0.097 ALL add 1.23 (1.04-1.46) 0.019 ALL add † rs12915 GALNAC4S- C 1.17 (0.98-1.40) 0.080 ALL add 1.13 (0.98-1.30) 0.088 ALL add † 6ST rs197922 GOSR2 A 1.29 (0.98-1.70) 0.071 F add 1.17 (1.01-1.34) 0.032 ALL add † rs2296434 HPS1 G 1.39 (1.01-1.90) 0.042 ALL add 1.34 (0.96-1.85) 0.082 M add † rs1060446 HPSE2 C 1.27 (1.07-1.50) 0.006 ALL add 1.14 (1.00-1.31) 0.052 ALL add † rs3739998 KIAA1462 G 1.26 (0.96-1.65) 0.093 F add 1.30 (1.06-1.61) 0.012 F add † rs3110234 LIFR T 1.19 (0.96-1.46) 0.066 ALL gen 1.17 (0.99-1.39) 0.070 ALL gen † rs28756981 MLH3 T 3.23 (1.10-9.50) 0.033 M add 4.58 (1.28-16.33) 0.019 M add † rs11051410 none G 1.22 (1.01-1.46) 0.038 ALL add 1.16 (1.00-1.34) 0.045 ALL add † rs1023899 none A 1.82 (1.19-2.78) 0.006 M add 1.40 (0.99-1.97) 0.059 M add † rs2959189 none G 1.59 (1.10-2.30) 0.014 ALL dom 1.27 (0.97-1.67) 0.085 ALL dom † rs10622 none T 1.27 (0.98-1.65) 0.066 ALL rec 1.28 (1.04-1.57) 0.018 ALL rec † rs7736962 none A 1.30 (1.01-1.67) 0.044 ALL rec 1.30 (0.98-1.72) 0.064 M rec † rs4706769 none T 1.17 (0.99-1.39) 0.067 ALL add 1.26 (1.04-1.53) 0.017 M add † rs3196714 ODAM T 1.45 (0.95-2.23) 0.085 ALL dom 1.32 (0.95-1.82) 0.095 ALL dom † rs1151640 OR13G1 C 1.34 (1.12-1.60) 0.001 ALL add 1.16 (1.01-1.33) 0.042 ALL add † rs11219508 OR8G2 C 1.45 (0.98-2.15) 0.065 F dom 1.34 (1.01-1.78) 0.042 F dom † rs2278586 OXER1 C 1.37 (0.98-1.91) 0.063 F add 1.35 (1.06-1.72) 0.014 F add † rs2970871 PPARGC1A C 1.17 (0.98-1.40) 0.080 ALL add 1.26 (0.98-1.61) 0.072 ALL dom † rs3750533 PRPF4 T 1.21 (0.97-1.52) 0.099 M add 1.20 (0.98-1.47) 0.076 M add † rs2297322 SLC15A1 C 1.44 (1.02-2.04) 0.037 M add 1.32 (0.98-1.76) 0.066 M add † rs2072549 SLC7A4 A 1.24 (1.00-1.53) 0.046 ALL add 1.17 (0.98-1.39) 0.079 ALL add † rs1785934 STATIP1 C 1.36 (0.98-1.88) 0.067 M dom 1.25 (1.02-1.53) 0.029 ALL dom † rs11735477 TKTL2 A 1.35 (1.04-1.75) 0.026 ALL dom 1.28 (0.95-1.72) 0.098 M dom † rs1042589 TPO C 1.24 (0.99-1.56) 0.061 M add 1.19 (1.04-1.36) 0.011 ALL add † rs1108225 TRPM3 A 1.23 (1.00-1.50) 0.048 ALL add 1.23 (1.05-1.45) 0.012 ALL add † rs10083789 USP31 A 1.22 (1.01-1.46) 0.036 ALL add 1.20 (1.04-1.39) 0.012 ALL add † rs35305327 WDR31 A 3.64 (1.04-12.75) 0.043 ALL add 2.48 (1.13-5.46) 0.023 ALL add † rs1465789 ZNF132 G 1.21 (0.98-1.50) 0.080 M add 1.19 (0.99-1.43) 0.071 M add † rs2017252 ZNF273 A 1.17 (0.99-1.39) 0.066 ALL add 1.18 (1.03-1.35) 0.017 ALL add † rs2884554 ZNF714 G 1.25 (0.97-1.61) 0.079 ALL add 1.19 (0.99-1.44) 0.063 ALL add † rs3027309 ALOX12B T 1.27 (1.02-1.59) 0.035 ALL add 1.18 (0.99-1.41) 0.068 ALL add ‡ rs2296436 HPS1 T 1.36 (0.99-1.85) 0.054 ALL add 1.32 (0.95-1.82) 0.095 M add ‡ rs1042636 CASR G 1.64 (0.94-2.86) 0.082 F add 1.30 (1.00-1.70) 0.047 ALL add ‡ rs1376251 TAS2R50 C 1.26 (1.05-1.52) 0.014 ALL add 1.23 (1.07-1.41) 0.004 ALL add ‡ rs12102203 RC3 G 1.38 (1.15-1.64) <0.001 ALL add 1.18 (1.03-1.35) 0.014 ALL add ‡ rs2286394 WDR55 T 1.24 (1.01-1.53) 0.037 ALL add 1.18 (1.00-1.39) 0.044 ALL add ‡ rs2307469 EIF2AK2 C 1.48 (0.95-2.32) 0.086 ALL add 1.71 (1.17-2.51) 0.006 ALL add ‡ rs3213646 MGC16943 C 1.22 (0.97-1.53) 0.092 M add 1.18 (0.98-1.43) 0.076 M add ‡ rs5985 F13A1 A 1.23 (1.01-1.51) 0.040 ALL add 1.21 (1.04-1.41) 0.013 ALL add ‡ Chr2: 37081301 KIAA1414 G 1.54 (1.07-2.20) 0.019 ALL add 1.59 (1.19-2.12) 0.002 ALL add ‡§ rs1042164 IER2 T 1.31 (1.03-1.69) 0.028 ALL add 1.22 (0.98-1.52) 0.070 ALL add ‡ rs6761276 IL1F10 T 1.25 (1.03-1.50) 0.020 ALL add 1.23 (1.07-1.41) 0.004 ALL add ‡ rs6743376 IL1F10 C 1.24 (1.03-1.49) 0.024 ALL add 1.22 (1.06-1.40) 0.006 ALL add ‡ rs943133 LOC391102 A 1.24 (1.02-1.51) 0.030 ALL add 1.19 (1.02-1.38) 0.023 ALL add ‡ rs3130210 LOC442203 T 1.24 (1.01-1.53) 0.037 ALL add 1.29 (1.09-1.52) 0.002 ALL add ‡ rs3129196 LOC442203 A 1.25 (1.02-1.53) 0.035 ALL add 1.29 (1.10-1.52) 0.002 ALL add ‡ rs12510359 PALLD G 1.26 (1.05-1.51) 0.011 ALL add 1.22 (1.07-1.41) 0.004 ALL add ‡ rs7439293 PALLD A 1.21 (1.01-1.46) 0.042 ALL add 1.22 (1.06-1.40) 0.006 ALL add ‡|| rs3798220 LPA C 4.71 (0.00-0.00) <0.001 ALL add 1.76 (0.00-0.00) 0.014 ALL add ‡ rs10082504 MKI67 C 1.38 (1.03-1.84) 0.034 ALL add 1.26 (1.01-1.59) 0.043 ALL add ‡ rs4750685 MKI67 G 1.33 (0.98-1.81) 0.069 ALL add 1.26 (1.00-1.59) 0.054 ALL add ‡¶ rs3900940 MYH15 C 0.32 (0.97-1.78) 0.078 F add 1.31 (1.05-1.63) 0.015 F add ‡|| rs12145360 MYOM3 A 1.36 (0.98-1.90) 0.069 M add 1.59 (1.22-2.07) 0.001 M add ‡ rs12684749 NFIB A 2.59 (1.39-4.82) 0.003 ALL add 1.36 (0.95-1.96) 0.097 ALL add ‡ rs3808117 GRM8 T 1.58 (1.26-1.98) 0.000 ALL add 1.21 (1.02-1.44) 0.026 ALL add ‡ rs2277838 P2RXL1 A 1.27 (1.02-1.58) 0.032 ALL add 1.21 (1.02-1.44) 0.032 ALL add ‡ rs3813135 PGLYRP2 C 1.25 (0.96-1.63) 0.095 ALL dom 1.27 (1.04-1.55) 0.020 ALL dom ‡ rs211070 PRKG1 G 1.71 (1.06-2.76) 0.029 ALL add 1.42 (1.03-1.97) 0.034 ALL add ‡ rs619203 ROS1 C 1.31 (1.06-1.61) 0.012 ALL add 1.30 (1.11-1.52) 0.001 ALL add ‡ rs529038 ROS1 T 1.31 (1.07-1.61) 0.010 ALL add 1.31 (1.12-1.53) 0.001 ALL add ‡ rs17090921 SERPINA9 A 2.31 (1.14-4.66) 0.019 F rec 1.50 (0.94-2.38) 0.087 F rec ‡ rs11628722 SERPINA9 G 1.26 (0.99-1.60) 0.058 ALL add 1.17 (0.98-1.39) 0.091 ALL add ‡ rs4747647 TAF3 A 1.22 (1.02-1.47) 0.033 ALL add 1.15 (1.00-1.32) 0.056 ALL add ‡ rs1010 VAMP8 C 1.36 (1.13-1.64) 0.001 ALL add 1.25 (1.09-1.43) 0.002 ALL add ‡|| rs6685323 AQP10 T 1.33 (1.10-1.61) 0.003 ALL add 1.19 (1.03-1.38) 0.020 ALL add # rs6480771 DUSP13 G 1.20 (1.01-1.43) 0.084 ALL gen 1.07 (0.93-1.23) 0.063 ALL gen # rs887 FLJ42562 G 1.21 (1.01-1.46) 0.040 ALL add 1.17 (1.01-1.35) 0.032 ALL add # rs28711149 OR13G1 T 1.21 (1.01-1.45) 0.038 ALL add 1.29 (0.97-1.72) 0.083 ALL dom # rs1126799 TPO C 1.16 (0.98-1.37) 0.091 ALL add 1.22 (0.99-1.51) 0.064 ALL rec # SNP, single nucleotide polymorphism; CCF, Cleveland Clinic Foundation; USCF, University of California, San Francisco; OR, odds ratio; CI, confidence interval; *This column indicates the location of published results for the testing of the association for each SNP and incident coronary heart disease in the Atherosclerosis Risk in Communities cohort.; † Online supplemental table II, Meyer et al., “A GOSR2 variant is associated with hypertension”, Hypertension, 2008; ‡ Morrison et al.³³; §previously reported as Chr2: 37139448 in build 35; ||Bare et al.³⁴; ¶previously reported as Chr10: 129793007 in build 35; # not reported because good multiplex assays could not be made

TABLE 8 Descriptive information by race and GOSR2 genotype Whites (N = 9,861) Blacks (N = 3,528) ArgArg LysArg LysLys ArgArg LysArg LysLys (n = 4,264) (n = 4,398) (n = 1,199) P* (n = 1,698) (n = 1,494) (n = 336) P* Mean ± SD Age, y  54 ± 5.7  54 ± 5.7  54 ± 5.8 0.26  53 ± 5.7  53 ± 5.9  54 ± 5.8 0.01 SBP (mmHg)^(†) 115.5 ± 15.6  116.7 ± 16.1  116.6 ± 16.0  <0.01 125.4 ± 19.6  125.5 ± 20.4  128.5 ± 21.2  0.15 DBP (mmHg)^(†) 70.5 ± 9.6  70.9 ± 9.8  71.0 ± 9.9  0.09 78.5 ± 11.3 78.1 ± 12.0 79.2 ± 12.3 0.96 Waist circumference 95.5 ± 13.4 96.4 ± 13.5 95.8 ± 13.2 0.05 99.0 ± 15.5 98.8 ± 14.8 99.2 ± 14.6 0.88 (cm) Ln(triglycerides) 0.27 ± 0.50 0.29 ± 0.51 0.28 ± 0.53 0.15 0.09 ± 0.46 0.09 ± 0.48 0.10 ± 0.45 0.80 (mmol/L)^(‡) HDL cholesterol 1.3 ± 0.4 1.3 ± 0.4 1.3 ± 0.4 0.96 1.4 ± 0.4 1.4 ± 0.5 1.4 ± 0.5 0.13 (mmol/L) Glucose (mmol/L)^(§) 5.5 ± 0.5 5.5 ± 0.5 5.5 ± 0.5 0.93 5.5 ± 0.6 5.5 ± 0.5 5.4 ± 0.6 0.15 CA IMT (mm) 0.73 ± 0.18 0.74 ± 0.18 0.74 ± 0.17 0.02 0.74 ± 0.16 0.73 ± 0.16 0.75 ± 0.17 0.60 No. (%) Male 1,952 (46) 1,983 (45) 551 (46) 0.77 643 (38) 542 (36) 116 (35) 0.42 Hypertension 1,012 (24) 1,181 (27) 314 (26) <0.01 926 (55) 797 (53) 186 (56) 0.66 Diabetes  327 (8)  375 (9) 105 (9)  0.26 308 (19) 261 (18)  65 (20) 0.68 SD, standard deviation; CA, carotid artery; IMT, intima media thickness; *P values are for the differences between genotypes (F-test for continuous variables or X² test for categorical variables); ^(†)Excluding participants taking anti-hypertensive medications; ^(‡)among those who fasted for at least 8 hours; ^(§)among nondiabetics who fasted for at least 8 hours

TABLE 9 OR and 95% CI for the association between GOSR2 (Lys67Arg, rs197922), hypertension, and carotid artery thickness Whites (N = 9,822) Blacks (N = 3,513) n OR (95% CI)* P^(‡) n OR (95% CI)* P^(‡) Hypertension 2,506 1.09 (1.02 to 1.17) 0.01 1,909 0.96 (0.87 to 1.07) 0.47 Elevated SBP (≥75% tile) 2,531 1.08 (1.00 to 1.15)^(†) 0.04 909 1.04 (0.92 to 1.17)^(†) 0.52 Elevated DBP (≥75% tile) 2,606 1.08 (1.01 to 1.16)^(†) 0.02 904 1.03 (0.92 to 1.16)^(†) 0.57 Thick CA IMT^(§) (≥75% tile) 2,284 1.09 (1.01 to 1.17) 0.02 830 0.99 (0.88 to 1.13) 0.92 OR, odds ratio; CI, confidence interval; n, number of affected; SBP, systolic blood pressure; DBP, diastolic blood pressure; CA, carotid artery; IMT, intima media thickness; *adjusted for gender and age at baseline; ^(†)additionally adjusted for anti-hypertensive medication use; ^(‡)P is Wald test p-value; ^(§)N = 9,302 whites and 3,146 blacks

TABLE 10 UCSF1 Non- Risk- Risk- Case Control Case Allele Control marker rs Gene Allele Allele Samples** Samples** Freq* Allele Freq* hCV11623551 rs8073829 LOC731128 C T 754 971 0.88 0.85 hCV15885004 rs2277614 LRRC37A2 A G 753 970 0.04 0.03 hCV2275263 rs197912 LRRC37A2 A T 754 972 0.38 0.35 hCV2275272 rs197920 GOSR2 T C 721 861 0.32 0.29 hCV2275276 rs197925 GOSR2 A G 716 862 0.41 0.38 hCV2592654 rs1662577 LRRC37A2 A C 753 970 0.40 0.37 hCV2592662 rs2191033 GOSR2 G A 715 859 0.41 0.38 hCV2592715 rs3851792 LRRC37A2 A T 715 859 0.57 0.54 hCV2592759 rs8080126 LRRC37A2 A C 754 973 0.73 0.71 hCV26660340 rs4968246 LRRC37A2 G C 754 973 0.40 0.36 hCV26683367 rs9894300 LOC731128 G C 754 973 0.88 0.85 hCV26683368 rs2004580 LOC731128 C T 755 973 0.88 0.85 hCV29195255 rs8068715 LRRC37A2 C A 723 858 0.57 0.54 hCV29195260 rs3851798 LRRC37A2 A G 725 863 0.57 0.54 hCV2960489 rs3785889 GOSR2 G A 719 861 0.51 0.47 hCV31466171 rs10853085 LRRC37A2 G A 718 863 0.40 0.37 hCV341736 rs11653589 LRRC37A2 T C 724 860 0.58 0.54 hCV537525 rs197943 LRRC37A2 C A 754 971 0.06 0.04 hCV7451269 rs1662594 LRRC37A2 A G 725 861 0.39 0.36 hCV7480314 rs3851799 LRRC37A2 C T 724 862 0.58 0.54 hDV70751699 rs16941393 LRRC37A2 A T 755 973 0.92 0.90 hDV70751704 rs16941401 LRRC37A2 T A 752 972 0.92 0.90 hDV70751706 rs16941404 LRRC37A2 G C 754 968 0.20 0.18 hDV70977122 rs17616652 LRRC37A2 A G 752 973 0.92 0.89 r{circumflex over ( )}2 with hCV2275273 marker OR* OR95L* OR95U* P_value Strata Model (GOSR2) hCV11623551 1.28 1.05 1.56 0.014 AllvsAll add 0.043 hCV15885004 1.47 1.02 2.13 0.041 AllvsAll add 0.061 hCV2275263 1.17 1.02 1.35 0.026 AllvsAll add 0.851 hCV2275272 1.15 0.99 1.33 0.076 AllvsAll add 0.82 hCV2275276 1.15 1.00 1.33 0.057 AllvsAll add 0.737 hCV2592654 1.13 0.99 1.30 0.076 AllvsAll add 0.806 hCV2592662 1.16 1.01 1.34 0.041 AllvsAll add 0.739 hCV2592715 1.14 0.98 1.31 0.085 AllvsAll add 0.252 hCV2592759 1.14 0.98 1.32 0.095 AllvsAll add 0.015 hCV26660340 1.15 1.00 1.32 0.045 AllvsAll add 0.541 hCV26683367 1.28 1.05 1.56 0.014 AllvsAll add 0.043 hCV26683368 1.26 1.04 1.54 0.019 AllvsAll add 0.044 hCV29195255 1.14 0.99 1.32 0.066 AllvsAll add 0.254 hCV29195260 1.15 1.00 1.33 0.056 AllvsAll add 0.254 hCV2960489 1.16 1.00 1.33 0.044 AllvsAll add 0.512 hCV31466171 1.15 0.99 1.32 0.062 AllvsAll add 0.79 hCV341736 1.16 1.00 1.34 0.046 AllvsAll add 0.25 hCV537525 1.45 1.07 1.97 0.016 AllvsAll add 0.028 hCV7451269 1.13 0.98 1.31 0.088 AllvsAll add 0.796 hCV7480314 1.14 0.99 1.32 0.068 AllvsAll add 0.253 hDV70751699 1.22 0.96 1.55 0.098 AllvsAll add 0 hDV70751704 1.23 0.97 1.56 0.089 AllvsAll add 0 hDV70751706 1.17 0.99 1.39 0.068 AllvsAll add 0.453 hDV70977122 1.46 1.16 1.84 0.001 AllvsAll add 0.042 notes: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 11 Risk factors for MI in participants of three case-control studies Study 1 Study 2 Study 3 Cases Controls Cases Controls Cases Controls (n = 762) (n = 857) (n = 579) (n = 1159) (n = 475) (n = 619) Male, % 60 41 81 42 61 62 Age at enrollment, median (range) 62 (29-87) 65 (24-100) 66 (28-88) 58 (45-97) 60 (32-86) 58 (37-88) Age at MI, median (range) 52 (27-82) NA 57 (21-70) NA  53 (29-77)^(†) NA Smoking, % 66 45 68 40 73 54 Diabetes, % 20   0^(‡) 25   0^(‡) 38 10 Dyslipidemia^(§), % 84 53 84 61 95 56 Hypertension^(||), % 61 32 66 33 96 78 BMI (kg/m²), mean ± SD 28 ± 5 26 ± 5 28 ± 5 26 ± 5 31 ± 6 30 ± 7 ^(†)Data available for 254 cases. ^(‡)Individuals with diabetes were excluded from control group. ^(§)Dyslipidemia was defined in Study 1 and Study 2 to be self-reported history of a physician diagnosis of dyslipidemia or the use of lipid lowering prescription medication(s) and defined in Study 3 to be the use of lipid lowering prescription medication(s), LDL cholesterol >129 mg/dL, triglycerides >149 mg/dL or HDL cholesterol <45 mg/dL. ^(||)Hypertension was defined in Study 1 and Study 2 to be a self-reported history of a physician diagnosis of hypertension or use of antihypertensive prescription medication(s) and defined in Study 3 to be the use of antihypertensive prescription medication(s), systolic blood pressure >160 mmHg, or diastolic blood pressure >90 mmHg. NA; not applicable.

TABLE 12 Twenty-four SNPs associated with MI in Study 1 and Study 2 Study 1 Study 2 Risk Risk Risk Allele Allele P value SNP Gene Symbol Allele Freq. P value OR 95% CI Freq. (1-sided) OR 90% CI rs11568658 ABCC4 G 0.97 0.005 1.98 1.24-3.16 0.97 0.01 1.81 1.19-2.77 rs16875009 ADAMTS16 A 0.13 0.005 1.33 1.09-1.62 0.13 0.005 1.29 1.10-1.51 rs25651 ANPEP T 0.29 0.0001 1.36 1.17-1.58 0.31 0.02 1.17 1.03-1.33 rs439401 APOE T 0.35 0.03 1.17 1.01-1.35 0.37 0.01 1.19 1.05-1.35 rs867852 C1orf81 T 0.78 0.03 1.22 1.02-1.45 0.78 0.04 1.17 1.01-1.37 rs28372907 DHX33 A 0.18 0.03 1.21 1.02-1.44 0.18 0.01 1.22 1.05-1.42 rs11553576 EML3 T 0.60 0.03 1.17 1.02-1.35 0.60 0.03 1.16 1.02-1.31 rs1325920 ENO1 A 0.80 0.02 1.24 1.03-1.48 0.80 0.007 1.26 1.08-1.48 rs31208 FAM71B G 0.11 0.03 1.27 1.03-1.57 0.12 0.006 1.30 1.09-1.55 rs3793456 FXN G 0.56 0.01 1.20 1.05-1.39 0.55 0.03 1.15 1.02-1.30 rs10890 FXN T 0.43 0.004 1.23 1.07-1.42 0.43 0.03 1.15 1.02-1.30 rs35410698 HLA-DPB2 G 0.93 0.02 1.43 1.06-1.91 0.94 0.006 1.53 1.16-2.03 rs1136141 HSPA8 G 0.86 0.05 1.24 1.00-1.53 0.86 0.02 1.26 1.05-1.52 rs7928656 KCTD14 A 0.84 0.04 1.23 1.01-1.51 0.84 0.004 1.32 1.11-1.57 rs3740918 KIRREL3 G 0.69 0.003 1.26 1.08-1.46 0.70 0.01 1.20 1.05-1.37 rs725660 LOC388553 A 0.34 0.006 1.23 1.06-1.42 0.35 0.0009 1.26 1.12-1.43 rs3798220 LPA C 0.02 0.04 1.59 1.03-2.48 0.02 0.008 1.72 1.19-2.49 rs11711953 MAP4 T 0.07 0.03 1.34 1.03-1.73 0.07 0.01 1.35 1.09-1.67 rs4907956 OLFM3 G 0.60 0.03 1.18 1.02-1.36 0.61 0.01 1.19 1.05-1.34 rs2290819 PTPRM T 0.38 0.03 1.17 1.01-1.35 0.38 0.008 1.20 1.06-1.35 rs3204635 STAC3 A 0.25 0.02 1.20 1.03-1.40 0.26 0.03 1.16 1.02-1.33 rs1866389 THBS4 C 0.20 0.03 1.21 1.02-1.43 0.20 0.03 1.19 1.03-1.37 rs3812475 TRMT12 T 0.50 0.03 1.16 1.01-1.34 0.52 0.04 1.13 1.01-1.28 rs862708 ZNF304 C 0.02 0.003 1.88 1.24-2.83 0.03 0.03 1.45 1.05-2.00

TABLE 13 Genotypic association of five SNPs in Study 3 SNP Cases Controls Age and Sex adjusted Fully Adjusted (gene symbol) Genotype n (%) n (%) OR 90% CI P value OR 90% CI P value rs1325920 AA 327 (71) 394 (65) 1.61 0.92-2.81 0.08 1.28 0.62-2.62 0.3 (ENO1) GA 120 (26) 186 (31) 1.25 0.70-2.22 0.3 1.20 0.57-2.54 0.3 GG 14 (3) 27 (4) ref ref Additive 1.28 1.06-1.55 0.01 1.09 0.85-1.38 0.3 rs10890 TT 117 (25)  98 (16) 1.52 1.14-2.04 0.009 1.49 1.02-2.18 0.04 (FXN) CT 201 (44) 325 (54) 0.79 0.62-0.99 0.9 0.85 0.63-1.16 0.8 CC 143 (31) 183 (30) ref ref Additive 1.18 1.02-1.37 0.03 1.18 0.98-1.42 0.07 rs3793456 GG 174 (38) 180 (30) 1.33 0.98-1.80 0.06 1.50 1.01-2.22 0.04 (FXN) AG 205 (45) 319 (53) 0.88 0.66-1.18 0.8 1.00 0.69-1.45 0.5 AA  78 (17) 107 (18) ref ref Additive 1.21 1.04-1.40 0.02 1.26 1.05-1.53 0.02 rs35410698 GG 426 (92) 539 (89) 1.56 1.09-2.22 0.02 2.07 1.31-3.27 0.004 (HLA-DPB2) GA 36 (8)  70 (11) ref ref Additive 1.46 1.03-2.06 0.04 1.79 1.14-2.81 0.02 rs3798220 CT 41 (9) 12 (2) 4.63 2.67-8.03 <0.001 3.52 1.85-6.69 0.001 (LPA) TT 416 (91) 573 (98) ref ref Additive 4.63 2.67-8.03 <0.001 3.52 1.85-6.69 0.001

TABLE 14 UCSF1 (S0012) Non- Case Control Risk Risk Case Control Allele Allele P- Marker gene Allele Allele Samples** Samples** Freq* Freq* OR* OR95L* OR95U* value* stratum Model hCV16065831 ENO1 T C 735 854 0.55 0.51 1.15 1.00 1.33 0.051 All additive hCV25996298 SLC45A1 T G 734 855 0.82 0.80 1.16 0.97 1.39 0.095 All additive hCV3086961 RERE C A 735 856 0.81 0.78 1.27 1.07 1.52 0.007 All additive hCV3087016 RERE C A 736 848 0.80 0.77 1.19 1.00 1.41 0.050 All additive hCV32055477 RERE G A 733 845 0.81 0.77 1.31 1.10 1.56 0.002 All additive hCV32055625 T C 733 852 0.82 0.78 1.26 1.05 1.50 0.011 All additive hCV32055654 G A 737 853 0.31 0.27 1.19 1.02 1.39 0.024 All additive hCV8824394 RERE T G 736 853 0.82 0.79 1.21 1.01 1.44 0.037 All additive hCV8881160 RERE C T 732 852 0.92 0.89 1.38 1.08 1.77 0.009 All additive hCV11398434 RERE C T 736 854 0.81 0.77 1.28 1.07 1.52 0.006 All additive hCV11398437 RERE C T 726 836 0.82 0.79 1.28 1.07 1.54 0.007 All additive hCV1188747 RERE G C 737 854 0.58 0.53 1.21 1.05 1.39 0.007 All additive hCV29819064 RERE C T 737 854 0.81 0.78 1.24 1.04 1.48 0.015 All additive hCV2987229 RERE C T 735 853 0.55 0.52 1.15 1.00 1.32 0.054 All additive hCV2987250 RERE G C 737 854 0.81 0.77 1.24 1.04 1.47 0.015 All additive hCV30233466 RERE G A 736 856 0.56 0.52 1.17 1.02 1.35 0.026 All additive hCV30287627 RERE T A 735 854 0.60 0.56 1.16 1.01 1.33 0.039 All additive hCV30467730 RERE T C 732 855 0.80 0.76 1.25 1.05 1.49 0.011 All additive hCV3086932 RERE G T 675 785 0.77 0.72 1.27 1.07 1.52 0.007 All additive hCV3086950 RERE A G 737 856 0.80 0.76 1.26 1.06 1.50 0.008 All additive hCV3086983 RERE T C 734 851 0.19 0.17 1.22 1.02 1.46 0.034 All additive hCV32055474 RERE G C 736 852 0.81 0.77 1.28 1.07 1.52 0.006 All additive hCV32055581 RERE A G 736 854 0.29 0.26 1.16 0.99 1.35 0.065 All additive hCV32055596 RERE G A 735 854 0.82 0.79 1.26 1.05 1.51 0.012 All additive hCV8379452 T C 737 853 0.56 0.51 1.19 1.04 1.37 0.012 All additive hCV8824244 ENO1 T C 735 851 0.81 0.79 1.19 0.99 1.42 0.063 All additive hCV8824248 ENO1 A G 736 855 0.82 0.79 1.20 1.01 1.44 0.042 All additive UCSF2 (S0061) Case Control r2 with Case Control Allele Allele hCV8824241 Marker Samples** Samples** Freq* Freq* OR* OR95L* OR95U* P-value* stratum Model (ENO1)*** hCV16065831 558 1152 0.56 0.52 1.18 1.02 1.36 0.0225 All additive 0.238 hCV25996298 555 1152 0.82 0.79 1.24 1.03 1.48 0.0211 All additive 0.214 hCV3086961 558 1154 0.82 0.77 1.34 1.12 1.60 0.0016 All additive 0.451 hCV3087016 558 1145 0.81 0.77 1.26 1.06 1.51 0.0105 All additive 0.416 hCV32055477 555 1149 0.82 0.77 1.33 1.11 1.59 0.0019 All additive 0.442 hCV32055625 557 1153 0.82 0.78 1.27 1.07 1.52 0.0077 All additive 0.596 hCV32055654 557 1153 0.31 0.29 1.35 0.97 1.88 0.0739 All recessive 0.059 hCV8824394 557 1154 0.82 0.78 1.28 1.06 1.53 0.0084 All additive 0.342 hCV8881160 558 1152 0.91 0.89 1.30 1.02 1.65 0.0324 All additive 0.327 hCV11398434 0.458 hCV11398437 0.45 hCV1188747 0.171 hCV29819064 0.442 hCV2987229 0.102 hCV2987250 0.416 hCV30233466 0.162 hCV30287627 0.149 hCV30467730 0.418 hCV3086932 0.38 hCV3086950 0.425 hCV3086983 0.025 hCV32055474 0.451 hCV32055581 0.047 hCV32055596 0.548 hCV8379452 0.157 hCV8824244 0.885 hCV8824248 0.87 note: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP ***based on UCSF1 Study design in UCSF1 and UCSF2: MI cases vs No CHD controls Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

TABLE 15 UCSF1 (S0012) Non Control Case Control Risk Risk Case Sam- Allele Allele P- Marker gene Allele Allele Samples** ples** Freq* Freq* OR* OR95L* OR95U* value* stratum Model hCV29033518 A T 737 854 0.09 0.07 1.28 0.99 1.64 0.0569 additive ALL_ALL hCV472000 TJP2 G A 734 853 0.10 0.07 1.33 1.03 1.70 0.0263 additive ALL_ALL hCV28008078 FXN C T 735 855 0.58 0.54 1.18 1.02 1.35 0.0219 additive ALL_ALL hCV30586985 FXN A G 736 855 0.60 0.55 1.23 1.06 1.41 0.0047 additive ALL_ALL hCV27970553 TJP2 T C 731 850 0.43 0.40 1.17 1.01 1.35 0.0344 additive ALL_ALL hCV7442005 TJP2 G A 737 851 0.49 0.44 1.22 1.06 1.40 0.0065 additive ALL_ALL hCV1463112 C T 734 853 0.59 0.55 1.16 1.01 1.34 0.0333 additive ALL_ALL hCV15892430 FXN C T 731 849 0.56 0.51 1.23 1.07 1.42 0.0038 additive ALL_ALL hCV1463224 FXN T C 737 854 0.49 0.43 1.25 1.08 1.44 0.0022 additive ALL_ALL hCV1463222 FXN C T 730 856 0.49 0.43 1.26 1.10 1.46 0.0011 additive ALL_ALL hCV11761245 TJP2 C T 735 855 0.48 0.43 1.21 1.05 1.39 0.0071 additive ALL_ALL hCV1463184 FXN T C 735 853 0.81 0.79 1.73 1.06 2.83 0.0289 dominant ALL_ALL hCV1844077 TJP2 G A 736 855 0.75 0.72 1.19 0.98 1.45 0.0863 recessive ALL_ALL UCSF2 (S0061) Case Control r2 with Case Control Allele Allele hCV1463226 Marker Samples** Samples** Freq* Freq* OR* OR95L* OR95U* P-value* stratum Model (FXN)*** hCV29033518 558 1152 0.10 0.08 1.23 0.96 1.58 0.0977 add ALL_ALL 0.042 hCV472000 557 1150 0.09 0.07 1.30 0.98 1.71 0.0653 dom ALL_ALL 0.057 hCV28008078 0.446 hCV30586985 0.572 hCV27970553 0.237 hCV7442005 0.325 hCV1463112 0.411 hCV15892430 0.435 hCV1463224 0.99 hCV1463222 0.989 hCV11761245 0.343 hCV1463184 0.196 hCV1844077 0 note: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP ***based on UCSF1 Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

TABLE 16 UCSF1 Case Case Control Allele Control Allele marker rs Gene RiskAllele NonRiskAllele Samples** Samples** Freq* Freq* hCV1188731 rs4908514 RERE T C 730 793 0.82 0.79 hCV1188735 rs10864366 RERE C T 734 793 0.82 0.79 hCV15967490 rs2292242 SLC45A1 T C 728 795 0.59 0.56 hCV27157435 rs7513420 RERE C T 735 794 0.60 0.57 hCV27157439 rs10779704 RERE C A 729 783 0.60 0.57 hCV27884601 rs4908776 RERE C T 734 793 0.82 0.79 hCV27958354 rs4908762 RERE T C 731 794 0.80 0.77 hCV28023091 rs4908773 RERE C T 736 792 0.83 0.79 hCV29368919 rs4908513 RERE C T 729 796 0.83 0.79 hCV2966448 rs1064826 RERE A G 734 790 0.28 0.25 hCV29873524 rs7533113 RERE T C 725 793 0.82 0.79 hCV29945430 rs7517436 RERE T G 734 789 0.82 0.78 hCV3086948 rs10864361 RERE C T 734 794 0.59 0.56 hCV3087000 rs1463055 RERE A G 736 796 0.81 0.77 hCV3087003 rs6577500 RERE C G 734 793 0.80 0.77 hCV3087008 rs12136689 RERE C A 723 794 0.33 0.29 hCV3087015 rs11121198 RERE G C 735 792 0.81 0.77 hCV32055527 rs10864364 RERE A C 736 795 0.83 0.79 hCV32055595 rs6577524 RERE T C 734 792 0.83 0.79 hCV529178 rs301811 RERE T C 732 789 0.81 0.77 hCV597227 rs301809 RERE T C 736 793 0.81 0.77 hCV8823713 rs1472228 RERE T C 736 791 0.82 0.79 hCV8824424 rs1058790 RERE A G 735 793 0.82 0.79 hCV8824425 rs1058791 RERE A C 723 792 0.82 0.79 hCV8824453 rs1466654 SLC45A1 T G 732 790 0.57 0.53 hCV8881161 rs926951 RERE G A 734 789 0.80 0.77 hCV8881164 rs1150398 RERE T C 733 786 0.98 0.97 r{circumflex over ( )}2 with marker OR* OR95L* OR95U* P_value Strata Model hCV32055477 (RERE) hCV1188731 1.26 1.05 1.51 0.0141 AllvsAll add 0.689 hCV1188735 1.25 1.05 1.50 0.0148 AllvsAll add 0.705 hCV15967490 1.17 1.01 1.35 0.0367 AllvsAll add 0.167 hCV27157435 1.17 1.01 1.35 0.0351 AllvsAll add 0.358 hCV27157439 1.17 1.01 1.35 0.0369 AllvsAll add 0.35 hCV27884601 1.25 1.05 1.51 0.0148 AllvsAll add 0.64 hCV27958354 1.23 1.03 1.46 0.0207 AllvsAll add 0.896 hCV28023091 1.31 1.09 1.57 0.0044 AllvsAll add 0.714 hCV29368919 1.28 1.06 1.53 0.0087 AllvsAll add 0.691 hCV2966448 1.15 0.98 1.35 0.0971 AllvsAll add 0.071 hCV29873524 1.27 1.05 1.52 0.0117 AllvsAll add 0.701 hCV29945430 1.28 1.07 1.53 0.0076 AllvsAll add 0.641 hCV3086948 1.15 1.00 1.33 0.0496 AllvsAll add 0.345 hCV3087000 1.26 1.06 1.50 0.0096 AllvsAll add 0.897 hCV3087003 1.23 1.03 1.46 0.0202 AllvsAll add 0.907 hCV3087008 1.15 0.99 1.35 0.0673 AllvsAll add 0.106 hCV3087015 1.25 1.05 1.49 0.0125 AllvsAll add 0.901 hCV32055527 1.29 1.07 1.54 0.0067 AllvsAll add 0.699 hCV32055595 1.26 1.05 1.51 0.0149 AllvsAll add 0.693 hCV529178 1.23 1.04 1.47 0.0178 AllvsAll add 0.895 hCV597227 1.26 1.06 1.50 0.0096 AllvsAll add 0.897 hCV8823713 1.23 1.02 1.47 0.0276 AllvsAll add 0.698 hCV8824424 1.23 1.03 1.47 0.0230 AllvsAll add 0.444 hCV8824425 1.20 1.00 1.44 0.0441 AllvsAll add 0.435 hCV8824453 1.19 1.03 1.37 0.0187 AllvsAll add 0.149 hCV8881161 1.24 1.04 1.47 0.0167 AllvsAll add 0.889 hCV8881164 1.53 0.94 2.48 0.0848 AllvsAll add 0.088 notes: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 17 UCSF1 Case Case Control Allele marker rs Gene RiskAllele NonRiskAllele Samples** Samples** Freq* hCV28993059 rs4832179 A G 770 920 0.09 hCV2091649 rs12714147 VAMP5 G A 771 921 0.17 hCV8696079 rs960066 T G 723 864 0.21 hCV2091650 rs10206961 RNF181 T C 723 862 0.42 hCV11504800 rs10176176 T A 721 861 0.48 hCV8696050 rs1254901 VAMP8 G A 770 920 0.70 hCV11942442 rs1254898 GGCX C T 718 862 0.70 hCV2091669 rs11688233 T A 723 865 0.92 hCV2091674 rs6733550 TMEM150 G T 716 862 0.37 Control r{circumflex over ( )}2 with Allele hCV2091644 marker Freq* OR* OR95L* OR95U* P value Strata Model (VAMP8) hCV28993059 0.08 1.25 0.99 1.58 0.0653 All add 0.019 hCV2091649 0.15 1.17 0.97 1.41 0.0935 All add 0.277 hCV8696079 0.19 1.16 0.97 1.37 0.0986 All add 0.219 hCV2091650 0.39 1.14 0.99 1.31 0.0706 All add 0.648 hCV11504800 0.44 1.17 1.02 1.35 0.0291 All add 0.784 hCV8696050 0.66 1.22 1.06 1.41 0.0072 All add 0.323 hCV11942442 0.66 1.18 1.02 1.38 0.0272 All add 0.307 hCV2091669 0.90 1.39 1.08 1.78 0.0102 All add 0.064 hCV2091674 0.34 1.14 0.99 1.33 0.0755 All add 0.364 notes: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 18 UCSF1 Case Control Case Allele marker rs Gene RiskAllele NonRiskAllele Samples** Samples** Freq* hCV11846435 rs6929299 LPA T C 760 852 0.67 hCV207123 rs7771801 LPA C G 757 855 0.68 hCV25927459 rs3798221 LPA G T 752 855 0.83 hCV27462774 rs3127583 A G 735 797 0.16 hCV282793 rs11751605 LPA C T 761 855 0.16 hCV29322781 rs6921516 LPA G A 734 795 0.68 hCV29809835 rs9457880 A C 735 796 0.05 hCV29952522 rs9457931 LPAL2 G A 733 797 0.08 hCV30574599 rs7770628 LPA C T 728 794 0.49 hCV3201490 rs1321195 LPA G A 735 795 0.87 hCV334752 rs6939089 LPA T C 758 853 0.68 hDV70715669 rs16891445 T A 735 795 0.05 hDV70973697 rs17593921 SLC22A3 C T 735 796 0.98 hCV31161091 rs3127573 SLC22A2 G A 733 788 0.13 hCV1550877 rs6919346 LPA C T 759 851 0.85 hCV2335281 rs519118 SLC22A3 T G 733 796 0.54 hCV3111822 rs316025 SLC22A2 T C 735 794 0.28 hCV561574 rs624319 SLC22A3 G A 733 796 0.55 r{circumflex over ( )}2 with Control Allele hCV25930271 marker Freq* OR* OR95L* OR95U* P value Strata Model (LPA) hCV11846435 0.61 1.26 1.09 1.46 0.0018 All add 0.01 hCV207123 0.63 1.24 1.07 1.44 0.0038 All add 0.009 hCV25927459 0.79 1.28 1.07 1.53 0.0058 All add 0.004 hCV27462774 0.13 1.26 1.02 1.54 0.0304 All add 0.004 hCV282793 0.14 1.19 0.98 1.43 0.0780 All add 0.005 hCV29322781 0.63 1.24 1.07 1.45 0.0044 All add 0.008 hCV29809835 0.04 1.37 0.96 1.96 0.0828 All add 0 hCV29952522 0.06 1.52 1.15 2.01 0.0030 All add 0.352 hCV30574599 0.45 1.17 1.02 1.35 0.0281 All add 0.014 hCV3201490 0.85 1.26 1.02 1.54 0.0292 All add 0.004 hCV334752 0.63 1.24 1.08 1.44 0.0032 All add 0.009 hDV70715669 0.04 1.46 1.02 2.08 0.0378 All add 0 hDV70973697 0.97 1.62 1.01 2.61 0.0475 All add 0 hCV31161091 0.11 1.27 1.00 1.61 0.0541 All dom 0.004 hCV1550877 0.83 1.24 1.00 1.53 0.0519 All rec 0.004 hCV2335281 0.52 1.29 1.03 1.61 0.0284 All rec 0.021 hCV3111822 0.26 1.42 0.95 2.12 0.0857 All rec 0.005 hCV561574 0.52 1.29 1.03 1.61 0.0276 All rec 0.021 notes: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP Study design in UCSF1: MI cases vs No CHD controls

TABLE 19 Meta-analysis of UCSF1 and UCSF2 myocardial infarction (MI) risk Non- Case Control Risk Risk Case Control Allele Allele marker Gene Chr Allele Allele Samples** Samples** Freq* Freq* OR* 95% CI* P value* hCV11846435 LPA 6 T C 1329 1994 0.67 0.63 1.22 1.10-1.36 0.0001 hCV1550877 LPA 6 C T 1327 2003 0.84 0.82 1.17 1.02-1.34 0.0203 hCV207123 LPA 6 C G 1331 2010 0.68 0.65 1.17 1.05-1.30 0.0034 hCV2335281 SLC22A3 6 T G 1306 1952 0.53 0.51 1.19 1.01-1.39 0.0324 hCV25927459 LPA 6 G T 1325 2008 0.82 0.80 1.16 1.02-1.32 0.0198 hCV25930271 LPA 6 C T 1338 2015 0.03 0.02 1.66 1.21-2.26 0.0015 hCV27422538 LPA 6 C G 1335 2015 0.80 0.77 1.25 1.10-1.41 0.0004 hCV27462774 6 A G 1308 1954 0.15 0.13 1.18 1.03-1.36 0.0214 hCV282793 LPA 6 C T 1334 2010 0.16 0.14 1.20 1.04-1.37 0.0106 hCV29322781 LPA 6 G A 1307 1949 0.68 0.65 1.16 1.04-1.29 0.0063 hCV29952522 LPAL2 6 G A 1307 1952 0.08 0.06 1.36 1.12-1.65 0.0020 hCV30574599 LPA 6 C T 1298 1944 0.48 0.46 1.09 0.99-1.21 0.0824 hCV3111822 SLC22A2 6 T C 1308 1949 0.28 0.26 1.12 1.00-1.25 0.0496 hCV31161091 SLC22A2 6 G A 1307 1942 0.13 0.11 1.20 1.03-1.39 0.0202 hCV3201490 LPA 6 G A 1308 1951 0.88 0.85 1.27 1.09-1.47 0.0016 hCV334752 LPA 6 T C 1328 2006 0.68 0.64 1.17 1.06-1.30 0.0029 hCV561574 SLC22A3 6 G A 1307 1951 0.54 0.52 1.10 0.99-1.21 0.0676 hDV70973697 SLC22A3 6 C T 1308 1951 0.98 0.97 1.31 0.96-1.78 0.0930 myocardial infarction (MI) risk Lp(a) level marker Strata Model Samples** Estimate* 95% CI* P value* Strata Model hCV11846435 AllvsAll add 911 0.122 0.06-0.19 1.95E−04 AllvsAll add hCV1550877 AllvsAll add 914 0.190 0.11-0.27 2.73E−06 AllvsAll add hCV207123 AllvsAll add 915 0.076 0.01-0.14 0.0213 AllvsAll add hCV2335281 AllvsAll rec 892 0.093 0.03-0.15 0.0028 AllvsAll add hCV25927459 AllvsAll add 911 0.214 0.14-0.29 4.53E−08 AllvsAll add hCV25930271 AllvsAll add 916 0.706 0.51-0.91 7.59E−12 AllvsAll add hCV27422538 AllvsAll add 917 0.236 0.16-0.31 3.63E−10 AllvsAll add hCV27462774 AllvsAll add 893 0.164 0.07-0.26 5.34E−04 AllvsAll add hCV282793 AllvsAll add 915 0.148 0.06-0.24 0.0012 AllvsAll add hCV29322781 AllvsAll add 892 0.076 0.01-0.14 0.0239 AllvsAll add hCV29952522 AllvsAll add 892 0.308 0.18-0.44 3.07E−06 AllvsAll add hCV30574599 AllvsAll add 887 0.089 0.03-0.15 0.0050 AllvsAll add hCV3111822 AllvsAll add 892 0.070 0.00-0.14 0.0562 AllvsAll add hCV31161091 AllvsAll add 889 0.126 0.03-0.22 0.0127 AllvsAll add hCV3201490 AllvsAll add 893 0.233 0.14-0.32 4.54E−07 AllvsAll add hCV334752 AllvsAll add 911 0.073 0.01-0.14 0.0274 AllvsAll add hCV561574 AllvsAll add 891 0.099 0.04-0.16 0.0013 AllvsAll add hDV70973697 AllvsAll add 891 0.210 0.04-0.38 0.0177 AllvsAll add note: *Data for allele frequency, OR and P-value were provided for risk alleles in this table **Valid counts for each SNP Study design for MI endpoint: MI cases vs controls having no history of CHD in UCSF1 and UCSF2 Study design for Lp(a) level endpoint: all patients with available Lp(a) level in UCSF1 and UCSF2; Lp(a) level was transformed to Log10Lp(a)

TABLE 20 UCSF1(S0012) Non Case Control Risk Risk Case Control Allele Allele Marker Gene chr Allele Allele Samples** Samples** Freq* Freq* OR* 95% CI* P-value* stratum Model hCV22274679 TRMT12 8 C T 737 853 0.54 0.50 1.16 (1.01-1.34) 0.0344 All additive hCV11688401 OR2H1 6 G A 736 854 0.27 0.24 1.15 (0.98-1.35) 0.0833 All additive hDV70661573 ADAMTS1 5 T A 710 826 0.17 0.13 1.33 (1.09-1.62) 0.0048 All additive hCV11854426 KCNB2 8 T C 737 856 0.13 0.11 1.21 (0.97-1.50) 0.0837 All additive hCV2531730 CHKB 22 A T 732 851 0.41 0.38 1.15 (1.00-1.33) 0.0532 All additive hCV3259235 EIF4E3 3 A G 732 848 0.12 0.10 1.23 (0.99-1.53) 0.0640 All additive hCV904974 19 C T 729 852 0.39 0.35 1.17 (1.01-1.35) 0.0325 All additive hDV68873046 C20orf23 20 A T 736 852 0.98 0.97 1.70 (1.09-2.66) 0.0204 All additive UCSF2(S0061) Case Control Case Control Allele Allele Marker Samples** Samples** Freq* Freq* OR* 95% CI* P-value* stratum Model hCV22274679 574 1157 0.55 0.52 1.13 (0.98-1.30) 0.0832 All additive hCV11688401 558 1154 0.26 0.23 1.21 (0.98-1.48) 0.0705 All dominant hDV70661573 558 1153 0.17 0.13 1.29 (1.06-1.56) 0.0102 All additive hCV11854426 553 1138 0.14 0.12 1.22 (0.97-1.55) 0.0918 All dominant hCV2531730 557 1154 0.41 0.38 1.15 (0.99-1.33) 0.0659 All additive hCV3259235 557 1152 0.12 0.10 1.21 (0.96-1.52) 0.0996 All additive hCV904974 558 1151 0.41 0.37 1.19 (1.03-1.38) 0.0200 All additive hDV68873046 558 1154 0.98 0.97 1.52 (0.95-2.44) 0.0815 All additive notes: *allele frequency, OR, and p-value are for the risk allele **valid counts for each SNP Study design in UCSF1 and UCSF2: MI cases vs No CHD controls

TABLE 21 CHD Risk Reduction by Pravastatin in CARE According to SNP Genotypes EVENTS NONEVENT (Pravas- (Pravas- EVENTS NONEVENT P Gene End- tatin tatin (placebo (placebo P inter- Allele Allele1 Allele Allele2 SNP rs symbol point Strata arm) arm) arm) arm) value HR HR95L HR95U action 1 Freq. 2 Freq. hCV16189421 rs1048755 ATXN3 endpt1 TC + TT 65 526 62 496 0.9853 1 0.708 1.421 0.0830 T 0.24 C 0.76 hCV16189421 rs1048755 ATXN3 endpt1 CC 68 729 97 684 0.0101 0.67 0.488 0.907 0.0830 T 0.24 C 0.76 hCV25630686 PSMB9 endpt1 TC + TT 5 85 14 78 0.0453 0.35 0.127 0.978 0.0993 T 0.03 C 0.97 hCV25630686 PSMB9 endpt1 CC 128 1206 151 1134 0.0728 0.81 0.637 1.02 0.0993 T 0.03 C 0.97 hCV25631989 rs1135983 ATF6 endpt1 TC + TT 26 198 13 187 0.0761 1.83 0.939 3.555 0.0080 T 0.08 C 0.92 hCV25631989 rs1135983 ATF6 endpt1 CC 107 1044 145 1001 0.0099 0.72 0.561 0.924 0.0080 T 0.08 C 0.92 hCV25644901 ITGA9 endpt1 GA + GG 9 120 26 103 0.0029 0.32 0.148 0.674 0.0093 G 0.05 A 0.95 hCV25644901 ITGA9 endpt1 AA 124 1171 139 1111 0.2050 0.86 0.671 1.089 0.0093 G 0.05 A 0.95 hCV25651076 rs5743291 NOD2 endpt1 AG + AA 28 217 21 195 0.5467 1.19 0.676 2.096 0.0926 A 0.09 G 0.91 hCV25651076 rs5743291 NOD2 endpt1 GG 104 1068 144 1021 0.0061 0.7 0.546 0.904 0.0926 A 0.09 G 0.91 hCV25651174 rs9277356 HLA-DPB1 endpt1 GA + GG 76 641 79 625 0.7173 0.94 0.689 1.293 0.0684 G 0.30 A 0.70 hCV25651174 rs9277356 HLA-DPB1 endpt1 AA 57 643 86 585 0.0046 0.62 0.441 0.861 0.0684 G 0.30 A 0.70 hCV25767417 rs3803430 ALDH1A3 endpt1 GA + GG 3 52 14 67 0.0565 0.3 0.085 1.034 0.0897 G 0.02 A 0.98 hCV25767417 rs3803430 ALDH1A3 endpt1 AA 130 1239 151 1145 0.0703 0.81 0.637 1.018 0.0897 G 0.02 A 0.98 hCV25922320 rs12360861 CD6 endpt1 AG + AA 62 439 56 466 0.4063 1.17 0.812 1.673 0.0033 A 0.21 G 0.79 hCV25922320 rs12360861 CD6 endpt1 GG 70 850 109 745 0.0003 0.58 0.428 0.781 0.0033 A 0.21 G 0.79 hCV25922440 rs34362748 GALC endpt1 TC + TT 30 377 50 341 0.0139 0.57 0.36 0.891 0.0728 T 0.16 C 0.84 hCV25922440 rs34362748 GALC endpt1 CC 103 881 109 849 0.5029 0.91 0.697 1.194 0.0728 T 0.16 C 0.84 hCV25922816 rs36013429 PPOX endpt1 AG + AA 14 184 27 145 0.0118 0.44 0.229 0.832 0.0487 A 0.07 G 0.93 hCV25922816 rs36013429 PPOX endpt1 GG 119 1075 134 1045 0.2573 0.87 0.677 1.11 0.0487 A 0.07 G 0.93 hCV25926178 rs12882130 MARK3 endpt1 GC + GG 80 786 111 714 0.0060 0.67 0.502 0.891 0.0710 G 0.38 C 0.62 hCV25926178 rs12882130 MARK3 endpt1 CC 52 478 50 477 0.8351 1.04 0.707 1.536 0.0710 G 0.38 C 0.62 hCV25926771 rs4906321 MARK3 endpt1 CT + CC 79 778 114 711 0.0035 0.65 0.49 0.869 0.0316 C 0.31 T 0.69 hCV25926771 rs4906321 MARK3 endpt1 TT 53 482 47 478 0.6009 1.11 0.75 1.645 0.0316 C 0.31 T 0.69 hCV25927605 HLA-DPA1 endpt1 TC + TT 10 80 3 74 0.1082 2.88 0.792 10.466 0.0216 T 0.03 C 0.97 hCV25927605 HLA-DPA1 endpt1 CC 122 1206 162 1136 0.0067 0.72 0.571 0.914 0.0216 T 0.03 C 0.97 hCV25928135 ADAM12 endpt1 CT + CC 41 479 63 430 0.0091 0.59 0.4 0.878 0.0741 C 0.21 T 0.79 hCV25928135 ADAM12 endpt1 TT 92 785 97 756 0.5831 0.92 0.694 1.228 0.0741 C 0.21 T 0.79 hCV25941408 rs28497577 MYLK endpt1 TG + TT 18 238 38 208 0.0035 0.43 0.248 0.761 0.0191 T 0.10 G 0.90 hCV25941408 rs28497577 MYLK endpt1 GG 115 1052 125 1010 0.3660 0.89 0.691 1.146 0.0191 T 0.10 G 0.90 hCV25942539 rs2401751 PTPN21 endpt1 AG + AA 63 700 98 682 0.0067 0.65 0.47 0.886 0.0496 A 0.34 G 0.66 hCV25942539 rs2401751 PTPN21 endpt1 GG 70 559 62 511 0.8839 1.03 0.729 1.444 0.0496 A 0.34 G 0.66 hCV26000635 rs7020782 PAPPA endpt1 CA + CC 82 665 84 645 0.8006 0.96 0.709 1.304 0.0322 C 0.31 A 0.69 hCV26000635 rs7020782 PAPPA endpt1 AA 51 624 81 566 0.0024 0.58 0.409 0.824 0.0322 C 0.31 A 0.69 hCV2633049 rs2302006 CCL24 endpt1 GT + GG 48 440 47 443 0.8749 1.03 0.691 1.544 0.0812 G 0.20 T 0.81 hCV2633049 rs2302006 CCL24 endpt1 TT 85 849 117 771 0.0050 0.67 0.507 0.887 0.0812 G 0.20 T 0.81 hCV2658421 rs3176975 APOH endpt1 AC + AA 48 522 BO 494 0.0037 0.59 0.412 0.842 0.0496 A 0.23 C 0.77 hCV2658421 rs3176975 APOH endpt1 CC 84 769 84 718 0.6671 0.94 0.692 1.266 0.0496 A 0.23 C 0.77 hCV2741051 rs2230806 ABCA1 endpt1 TC + TT 66 645 62 593 0.9717 0.99 0.703 1.406 0.0576 T 0.28 C 0.72 hCV2741051 rs2230806 ABCA1 endpt1 CC 67 647 103 624 0.0038 0.63 0.467 0.864 0.0576 T 0.28 C 0.72 hCV2741083 rs4149313 ABCA1 endpt1 CT + CC 36 316 23 289 0.2143 1.39 0.826 2.351 0.0119 C 0.13 T 0.87 hCV2741083 rs4149313 ABCA1 endpt1 TT 97 976 142 927 0.0020 0.67 0.515 0.862 0.0119 C 0.13 T 0.87 hCV2932115 rs5517 KLK1 endpt1 CT + CC 75 591 77 566 0.7201 0.94 0.687 1.297 0.0755 C 0.27 T 0.73 hCV2932115 rs5517 KLK1 endpt1 TT 58 701 88 651 0.0050 0.62 0.447 0.867 0.0755 C 0.27 T 0.73 hCV2983035 rs9527026 KL endpt1 AG + AA 36 387 53 321 0.0110 0.58 0.378 0.882 0.0944 A 0.15 G 0.85 hCV2983035 rs9527026 KL endpt1 GG 97 903 110 893 0.3656 0.88 0.671 1.158 0.0944 A 0.15 G 0.85 hCV3026189 rs11739136 KCNIP1 endpt1 TC + TT 29 241 23 234 0.4448 1.24 0.716 2.14 0.0557 T 0.10 C 0.90 hCV3026189 rs11739136 KCNIP1 endpt1 CC 104 1050 142 984 0.0048 0.69 0.54 0.895 0.0557 T 0.10 C 0.90 hCV3068176 rs1801394 MTRR endpt1 AG + AA 100 908 110 873 0.3839 0.89 0.676 1.162 0.0609 A 0.46 G 0.54 hCV3068176 rs1801394 MTRR endpt1 GG 33 384 55 345 0.0062 0.55 0.355 0.842 0.0609 A 0.46 G 0.54 hCV3111721 rs33950747 NPHS1 endpt1 TC + TT 11 191 19 126 0.0160 0.4 0.191 0.844 0.0645 T 0.06 C 0.94 hCV3111721 rs33950747 NPHS1 endpt1 CC 121 1098 146 1088 0.1265 0.83 0.651 1.055 0.0645 T 0.06 C 0.94 hCV529706 rs428785 ADAMTS1 endpt1 CG + CC 55 569 80 476 0.0036 0.6 0.426 0.846 0.0611 C 0.24 G 0.76 hCV529706 rs428785 ADAMTS1 endpt1 GG 77 719 84 735 0.6603 0.93 0.685 1.271 0.0611 C 0.24 G 0.76 hCV529710 rs402007 ADAMTS1 endpt1 CG + CC 57 570 81 480 0.0052 0.62 0.44 0.866 0.0858 C 0.24 G 0.76 hCV529710 rs402007 ADAMTS1 endpt1 GG 76 720 84 737 0.6155 0.92 0.677 1.26 0.0858 C 0.24 G 0.76 hCV5478 rs1800574 TCF1 endpt1 TC + TT 11 75 4 76 0.0953 2.65 0.843 8.319 0.0175 T 0.03 C 0.97 hCV5478 rs1800574 TCF1 endpt1 CC 122 1217 161 1141 0.0067 0.72 0.571 0.914 0.0175 T 0.03 C 0.97 hCV549926 rs1057141 Tap1or endpt1 CT + CC 33 395 58 354 0.0042 0.54 0.35 0.822 0.0495 C 0.16 T 0.84 hCV549926 rs1057141 Tap1or endpt1 TT 99 894 107 857 0.3934 0.89 0.675 1.167 0.0495 C 0.16 T 0.84 hCV594695 rs45551939 SERPINA1 endpt1 AT + AA 19 115 11 92 0.3548 1.42 0.675 2.997 0.0813 A 0.04 T 0.96 hCV594695 rs45551939 SERPINA1 endpt1 TT 112 1169 154 1121 0.0055 0.71 0.555 0.904 0.0813 A 0.04 T 0.96 hCV598677 rs5370 EDN1 endpt1 TG + TT 44 518 70 459 0.0035 0.57 0.391 0.831 0.0339 T 0.22 G 0.78 hCV598677 rs5370 EDN1 endpt1 GG 89 774 93 759 0.7179 0.95 0.709 1.268 0.0339 T 0.22 G 0.78 hCV7441704 rs1800205 PPT1 endpt1 GA + GG 7 118 18 109 0.0354 0.39 0.164 0.938 0.0966 G 0.05 A 0.95 hCV7441704 rs1800205 PPT1 endpt1 AA 125 1169 147 1107 0.0868 0.81 0.64 1.031 0.0966 G 0.05 A 0.95 hCV7443062 rs897453 PEMT endpt1 TC + TT 102 897 107 865 0.5540 0.92 0.702 1.208 0.0186 T 0.45 C 0.55 hCV7443062 rs897453 PEMT endpt1 CC 31 395 57 350 0.0021 0.5 0.325 0.78 0.0186 T 0.45 C 0.55 hCV7475492 rs1138469 HSPG2 endpt1 TC + TT 23 156 22 185 0.5131 1.22 0.677 2.181 0.0988 T 0.07 C 0.93 hCV7475492 rs1138469 HSPG2 endpt1 CC 109 1132 142 1026 0.0072 0.71 0.553 0.912 0.0988 T 0.07 C 0.93 hCV7490135 rs1805082 NPC1 endpt1 CT + CC 85 924 126 866 0.0018 0.64 0.49 0.849 0.0207 C 0.47 T 0.53 hCV7490135 rs1805082 NPC1 endpt1 TT 48 363 39 345 0.4748 1.17 0.765 1.78 0.0207 C 0.47 T 0.53 hCV7494810 rs1058587 GDF15 endpt1 GC + GG 46 559 60 517 0.0017 0.56 0.389 0.804 0.0241 G 0.25 C 0.75 hCV7494810 rs1058587 GDF15 endpt1 CC 86 730 85 697 0.7657 0.96 0.708 1.289 0.0241 G 0.25 C 0.75 hCV7499212 rs1800127 LRP1 endpt1 TC*TT 5 63 14 56 0.0366 0.34 0.121 0.934 0.0831 T 0.02 C 0.98 hCV7499212 rs1800127 LRP1 endpt1 CC 128 1229 151 1158 0.0771 0.81 0.639 1.023 0.0831 T 0.02 C 0.98 hCV7514879 rs1800629 endpt1 AG + AA 33 403 55 361 0.0048 0.54 0.348 0.827 0.0538 A 0.17 G 0.83 hCV7514879 rs1800629 endpt1 GG 100 885 110 855 0.4029 0.89 0.679 1.168 0.0538 A 0.17 G 0.83 hCV7577801 rs11876 SLC9A3R2 endpt1 TC + TT 56 491 48 468 0.6023 1.11 0.753 1.629 0.0200 T 0.22 C 0.78 hCV7577801 rs11876 SLC9A3R2 endpt1 CC 77 798 117 741 0.0015 0.63 0.471 0.837 0.0200 T 0.22 C 0.78 hCV7618856 rs1143675 ITGA4 endpt1 CT + CC 4 19 1 33 0.0972 6.39 0.714 57.205 0.0287 C 0.01 T 0.99 hCV7618856 rs1143675 ITGA4 endpt1 TT 127 1264 163 1182 0.0114 0.74 0.588 0.935 0.0287 C 0.01 T 0.99 hCV783138 rs6046 F10 endpt1 AG + AA 31 258 4 242 0.4753 1.21 0.713 2.069 0.0600 A 0.11 G 0.89 hCV783138 rs6046 F10 endpt1 GG 101 1033 139 972 0.0051 0.69 0.537 0.896 0.0600 A 0.11 G 0.89 hCV783184 rs510335 endpt1 TG + TT 32 282 27 273 0.5952 1.15 0.688 1.918 0.0802 T 0.12 G 0.88 hCV783184 rs510335 endpt1 GG 100 1008 137 942 0.0053 0.69 0.536 0.897 0.0802 T 0.12 G 0.88 hCV7841642 rs11666735 FCAR endpt1 AG + AA 13 183 30 169 0.0103 0.43 0.222 0.817 0.0473 A 0.07 G 0.93 hCV7841642 rs11666735 FCAR endpt1 GG 120 1108 135 1048 0.1808 0.85 0.661 1.081 0.0473 A 0.07 C 0.93 hCV7900503 rs3732379 CX3CR1 endpt1 TC + TT 65 614 66 616 0.7875 0.95 0.679 1.341 0.0908 T 0.28 C 0.72 hCV7900503 rs3732379 CX3CR1 endpt1 CC 68 677 97 600 0.0051 0.64 0.471 0.875 0.0908 T 0.28 C 0.72 hCV795441 rs401502 IL12RB1 endpt1 GC + GG 81 690 79 649 0.8725 0.97 0.715 1.329 0.0296 G 0.32 C 0.68 hCV795441 rs401502 IL12PB1 endpt1 CC 52 596 86 565 0.0022 0.58 0.414 0.825 0.0296 G 0.32 C 0.68 hCV795442 rs375947 IL12RB1 endpt1 GA + GG 80 691 77 651 0.9472 0.99 0.724 1.353 0.0218 G 0.32 A 0.68 hCV795442 rs375947 IL12RB1 endpt1 AA 52 599 87 566 0.0016 0.58 0.408 0.812 0.0218 G 0.32 A 0.68 hCV8705506 rs5516 KLK1 endpt1 CG + CC 66 749 96 667 0.0032 0.62 0.456 0.854 0.0480 C 0.34 G 0.66 hCV8705506 rs5516 KLK1 endpt1 GG 67 543 69 550 0.9467 0.99 0.706 1.384 0.0480 C 0.34 G 0.66 hCV8708474 rs1800468 MGC4093 endpt1 TC + TT 30 212 23 194 0.5341 1.19 0.69 2.046 0.0851 T 0.09 C 0.91 hCV8708474 rs1800468 MGC4093 endpt1 CC 103 1068 142 1013 0.0062 0.7 0.545 0.905 0.0851 T 0.09 C 0.91 hCV8718197 rs1050998 CXCL16 endpt1 GA + GG 98 879 100 842 0.6535 0.94 0.71 1.24 0.0102 G 0.44 A 0.56 hCV8718197 rs1050998 CXCL16 endpt1 AA 33 409 65 376 0.0008 0.49 0.322 0.744 0.0102 G 0.44 A 0.56 hCV8726337 rs5498 ICAM1 endpt1 GA + GG 102 857 111 851 0.5198 0.92 0.7 1.198 0.0274 G 0.44 A 0.56 hCV8726337 rs5498 ICAM1 endpt1 AA 31 430 53 365 0.0031 0.51 0.329 0.798 0.0274 G 0.44 A 0.56 hCV8848630 rs7192 HLA-DRA endpt1 TG + TT 74 802 106 737 0.0054 0.66 0.487 0.883 0.0756 T 0.38 G 0.62 hCV8848630 rs7192 HLA-DRA endpt1 GG 59 485 58 477 0.9870 1 0.698 1.441 0.0756 T 0.38 G 0.62 hCV8851085 rs1042153 HLA-DPB1 endpt1 AG + AA 58 491 58 484 0.9498 0.99 0.687 1.422 0.0838 A 0.22 G 0.78 hCV8851085 rs1042153 HLA-DPB1 endpt1 GG 74 798 106 731 0.0049 0.65 0.485 0.878 0.0838 A 0.22 G 0.78 hCV8895373 rs1503185 PTPRJ endpt1 AG + AA 53 409 44 394 0.5323 1.14 0.762 1.694 0.0203 A 0.18 G 0.82 hCV8895373 rs1503185 PTPRJ endpt1 GG 80 882 120 820 0.0018 0.64 0.481 0.847 0.0203 A 0.18 G 0.82 hCV8901525 rs861539 KLC1 endpt1 AG + AA 88 759 86 734 0.9319 0.99 0.733 1.329 0.0204 A 0.37 G 0.63 hCV8901525 rs861539 KLC1 endpt1 GG 45 504 75 457 0.0025 0.57 0.39 0.818 0.0204 A 0.37 G 0.63 hCV8921288 rs1060621 GAPDH endpt1 CA + CC 36 440 73 403 0.0003 0.48 0.319 0.71 0.0008 C 0.20 A 0.80 hCV8921288 rs1060621 GAPDH endpt1 AA 97 815 85 786 0.5588 1.09 0.815 1.459 0.0008 C 0.20 A 0.80 hCV904973 rs7412 APOE endpt1 TC + TT 19 141 11 135 0.2198 1.59 0.757 3.348 0.0416 T 0.06 C 0.94 hCV904973 rs7412 APOE endpt1 CC 114 1149 154 1081 0.0059 0.71 0.559 0.907 0.0416 T 0.06 C 0.94 hCV9077561 rs1801274 FCGR2A endpt1 GA + GG 96 985 133 891 0.0027 0.67 0.515 0.87 0.0357 G 0.50 A 0.50 hCV9077561 rs1801274 FCGR2A endpt1 AA 36 300 32 325 0.4605 1.2 0.743 1.926 0.0357 G 0.50 A 0.50 hCV9494470 endpt1 TG + TT 33 407 54 365 0.0102 0.57 0.368 0.874 0.0957 T 0.17 G 0.83 hCV9494470 endpt1 GG 100 884 111 851 0.3255 0.87 0.666 1.144 0.0957 T 0.17 G 0.83 hCV9506149 rs1250259 FN1 endpt1 TA + TT 69 611 68 582 0.8631 0.97 0.695 1.357 0.0654 T 0.28 A 0.72 hCV9506149 rs1250259 FN1 endpt1 AA 64 678 97 634 0.0042 0.63 0.46 0.865 0.0654 T 0.28 A 0.72 hCV9604851 rs1805002 CCKBR endpt1 AG + AA 19 113 14 140 0.1884 1.59 0.797 3.171 0.0273 A 0.05 G 0.95 hCV9604851 rs1805002 CCKBR endpt1 GG 114 1178 151 1075 0.0046 0.7 0.552 0.898 0.0273 A 0.05 G 0.95 hCV2553030 rs11230562 CD6 endpt1 TC + CC 129 1179 154 1151 0.1178 0.83 0.657 1.048 0.0059 T 0.25 C 0.75 hCV2553030 rs11230562 CD6 endpt1 TT 3 107 11 63 0.0062 0.17 0.047 0.603 0.0059 T 0.25 C 0.75 hCV25637309 rs3204849 CCRL2 endpt1 AT + TT 109 1107 150 994 0.0013 0.67 0.522 0.8bb 0.0031 A 0.39 T 0.61 hCV25637309 rs3204849 CCRL2 endpt1 AA 24 184 15 219 0.0572 1.87 0.981 3.566 0.0031 A 0.39 T 0.61 hCV25640504 endpt1 TC + CC 113 1035 128 977 0.1795 0.84 0.653 1.083 0.0390 T 0.28 C 0.72 hCV25640504 endpt1 TT 12 194 28 175 0.0084 0.4 0.205 0.792 0.0390 T 0.28 C 0.72 hCV2769554 rs1805010 IL4R endpt1 GA + AA 101 1001 144 939 0.0021 0.67 0.52 0.865 0.0118 G 0.46 A 0.54 hCV2769554 rs1805010 IL4R endpt1 GG 32 287 21 274 0.1841 1.45 0.837 2.518 0.0118 G 0.46 A 0.54 hCV2822674 rs1801222 CUBN endpt1 AG + GG 123 1140 144 1097 0.137b 0.83 0.655 1.06 0.0448 A 0.32 G 0.68 hCV2822674 rs1801222 CUBN endpt1 AA 10 150 21 117 0.0120 0.38 0.179 0.806 0.0448 A 0.32 G 0.68 hCV2992252 rs6037651 SIGLEC1 endpt1 CT + TT 124 1089 140 1019 0.1532 0.84 0.658 1.068 0.0173 C 0.40 T 0.60 hCV2992252 rs6037651 SIGLEC1 endpt1 CC 8 196 25 193 0.0052 0.32 0.145 0.713 0.0173 C 0.40 T 0.60 hCV3187716 rs5186 AGTR1 endpt1 CA + AA 128 1176 143 1093 0.1486 0.84 0.661 1.065 0.0111 C 0.30 A 0.70 hCV3187716 rs5186 AGTR1 endpt1 CC 5 112 22 118 0.0061 0.26 0.097 0.679 0.0111 C 0.30 A 0.70 hCV3215409 rs267561 ITGA9 endpt1 GA + AA 118 1057 128 994 0.2979 0.88 0.682 1.124 0.0133 G 0.42 A 0.58 hCV3215409 rs267561 ITGA9 endpt1 GG 15 235 37 222 0.0026 0.4 0.218 0.723 0.0133 C 0.42 A 0.58 hCV3219460 rs1799983 NOS3 endpt1 TG + GG 124 1114 144 1065 0.1316 0.83 0.654 1.057 0.0495 T 0.35 G 0.65 hCV3219460 rs1799983 NOS3 endpt1 TT 9 177 21 149 0.0157 0.38 0.175 0.834 0.0495 T 0.35 G 0.65 hCV370782 rs9841174 SERPINI2 endpt1 CT + TT 113 1097 150 1022 0.0065 0.71 0.558 0.91 0.0938 C 0.38 T 0.62 hCV370782 rs9841174 SERPINI2 endpt1 CC 20 194 15 189 0.4473 1.3 0.664 2.532 0.0938 C 0.38 T 0.62 hCV7514870 rs1041981 LTA endpt1 AC + CC 121 1118 144 1094 0.1397 0.83 0.655 1.061 0.0624 A 0.33 C 0.67 hCV7514870 rs1041981 LTA endpt1 AA 12 172 21 122 0.0110 0.4 0.194 0.809 0.0624 A 0.33 C 0.67 hCV818008 rs5918 ITGB3 endpt1 CT + TT 126 1266 164 1194 0.0099 0.74 0.584 0.929 0.0236 C 0.15 T 0.85 hCV818008 rs5918 ITGB3 endpt1 CC 7 26 1 22 0.1271 5.11 0.628 41.557 0.0236 C 0.15 T 0.85 hCV8708473 rs1800469 TMEM91 endpt1 AG + GG 124 1153 145 1090 0.1014 0.82 0.644 1.04 0.0991 A 0.32 G 0.68 hCV8708473 rs1800469 TMEM91 endpt1 AA 9 139 20 125 0.0331 0.43 0.193 0.934 0.0991 A 0.32 G 0.68 hCV8709053 rs4880 SOD2 endpt1 GA + AA 105 954 117 928 0.3282 0.88 0.674 1.141 0.0636 G 0.50 A 0.50 hCV8709053 rs4880 SOD2 endpt1 GG 28 335 47 285 0.0077 0.53 0.331 0.845 0.0636 G 0.50 A 0.50 hCV8737990 rs419598 IL1RN endpt1 CT + TT 117 1193 157 1104 0.0035 0.7 0.551 0.89 0.0157 C 0.28 T 0.72 hCV8737990 rs419598 IL1RN endpt1 CC 15 96 8 103 0.1156 1.99 0.844 4.699 0.0157 C 0.28 T 0.72 hCV8784787 rs688976 endpt1 AC + CC 126 1234 163 1147 0.0088 0.73 0.581 0.925 0.0443 A 0.23 C 0.77 hCV8784787 rs688976 endpt1 AA 6 57 2 69 0.1452 3.29 0.663 16.304 0.0443 A 0.23 C 0.77 hCV8804621 rs1390938 SLC18A1 endpt1 AG + GG 125 1218 160 1132 0.0120 0.74 0.586 0.936 0.0805 A 0.25 G 0.75 hCV8804621 rs1390938 SLC18A1 endpt1 AA 8 69 4 80 0.2298 2.09 0.628 6.934 0.0805 A 0.25 G 0.75 hCV8851047 rs45614833 HLA-DPA1 endpt1 CT + TT 126 1229 158 1152 0.0224 0.76 0.602 0.962 0.0104 C 0.17 T 0.83 hCV8851047 rs45614833 HLA-DPA1 endpt1 CC 7 32 1 37 0.0779 6.59 0.81 53.622 0.0104 C 0.17 T 0.83 hCV8851065 rs9277343 HLA-DPA1 endpt1 GC + CC 120 1198 158 1120 0.0072 0.72 0.57 0.916 0.0322 G 0.28 C 0.72 hCV8851065 rs9277343 HLA-DPA1 endpt1 GG 13 90 7 98 0.1152 2.1 0.835 5.264 0.0322 G 0.28 C 0.72 hCV8851095 rs1042335 HLA-DPB1 endpt1 TC + CC 126 1216 157 1139 0.0229 0.76 0.603 0.963 0.0840 T 0.27 C 0.73 hCV8851095 rs1042335 HLA-DPB1 endpt1 TT 7 40 4 50 0.1712 2.37 0.688 8.198 0.0840 T 0.27 C 0.73 hCV9055799 rs3734311 IMPG1 endpt1 CG + GG 117 1040 142 1049 0.1628 0.84 0.658 1.073 0.0749 C 0.40 G 0.60 hCV9055799 rs3734311 IMPG1 endpt1 CC 15 247 23 166 0.0153 0.45 0.233 0.857 0.0749 C 0.40 G 0.60 hCV9596963 rs6115 SERPINA5 endpt1 GA + AA 106 1147 151 1098 0.0027 0.68 0.534 0.877 0.0181 G 0.32 A 0.68 hCV9596963 rs6115 SERPINA5 endpt1 GG 26 136 14 117 0.1985 1.53 0.8 2.934 0.0181 G 0.32 A 0.68 hCV997884 rs512770 endpt1 AG + GG 126 1241 162 1143 0.0079 0.73 0.578 0.921 0.0466 A 0 20 G 0.80 hCV997884 rs512770 endpt1 AA 5 42 2 63 0.1428 3.41 0.661 17.577 0.0466 A 0.20 G 0.80 hCV2983036 rs9527025 KL endpt1 CC 4 22 2 27 0.3494 2.25 0.412 12.278 0.0793 C 0.15 G 0.85 hCV2983036 rs9527025 KL endpt1 CG 32 363 51 293 0.0043 0.53 0.338 0.818 0.0793 C 0.15 G 0.85 hCV2983036 rs9527025 KL endpt1 GG 97 906 112 891 0.2806 0.86 0.656 1.13 0.0793 C 0.15 G 0.85 hCV3135085 rs10795446 CUBN endpt1 GG 10 147 21 145 0.0690 0.5 0.234 1.056 0.0932 G 0.33 T 0.67 hCV3135085 rs10795446 CUBN endpt1 GT 64 554 61 532 0.9477 1.01 0.712 1.437 0.0932 G 0.33 T 0.67 hCV3135085 rs10795446 CUBN endpt1 TT 57 575 82 529 0.0116 0.65 0.462 0.908 0.0932 G 0.33 T 0.67 hCV3275199 rs2069885 IL9 endpt1 AA 5 28 2 21 0.5551 1.64 0.318 8.446 0.0775 A 0.13 G 0.87 hCV3275199 rs2069885 IL9 endpt1 AG 18 310 35 257 0.0060 0.45 0.255 0.796 0.0775 A 0.13 G 0.87 hCV3275199 rs2069885 IL9 endpt1 GG 109 947 128 937 0.2088 0.85 0.658 1.096 0.0775 A 0.13 G 0.87 hCV342590 rs6030 F5 endpt1 CC 15 123 13 130 0.6256 1.2 0.572 2.529 0.0995 C 0.31 T 0.69 hCV342590 rs6030 F5 endpt1 CT 44 553 7.1 519 0.0034 0.57 0.394 0.832 0.0995 C 0.31 T 0.69 hCV342590 rs6030 F5 endpt1 TT 74 613 78 566 0.4490 0.88 0.643 1.216 0.0995 C 0.31 T 0.69 hCV435368 rs2812 PECAM1 endpt1 TT 40 272 44 270 0.6056 0.89 0.582 1.371 0.0948 T 0.47 C 0.53 hCV435368 rs2812 PECAM1 endpt1 IC 56 649 86 573 0.0028 0.6 0.428 0.838 0.0948 T 0.47 C 0.53 hCV435368 rs2812 PECAM1 endpt1 CC 37 369 34 373 0.7363 1.08 0.68 1.726 0.0948 T 0.47 C 0.53 hCV11170747 rs2066853 AHR endpt1 GG 112 1008 128 982 0.2728 0.87 0.673 1.118 0.0356 A 0.11 G 0.89 hCV11170747 rs2066853 AHR endpt1 AG + AA 20 283 36 235 0.0036 0.44 0.256 0.767 0.0356 A 0.11 G 0.89 hCV11181829 rs5713 ACSM3 endpt1 TT 124 1259 161 1189 0.0112 0.74 0.584 0.933 0.0735 C 0.01 T 0.99 hCV11181829 rs5713 ACSM3 endpt1 CT + CC 8 23 4 26 0.2129 2.14 0.646 7.125 0.0735 C 0.01 T 0.99 hCV11225994 rs1853021 LPA endpt1 GG 92 973 130 894 0.0026 0.66 0.508 0.866 0.0671 A 0.13 G 0.87 hCV11225994 rs1853021 LPA endpt1 AG + AA 37 311 34 314 0.7086 1.09 0.686 1.741 0.0671 A 0.13 G 0.87 hCV11438723 rs1877273 WWOX endpt1 TT 0 12 3 13 0.9973 0 0 . 0.0772 T 0.10 C 0.90 hCV11438723 rs1877273 WWOX endpt1 TC + CC 133 1270 162 1194 0.0368 0.78 0.623 0.985 0.0772 T 0.10 C 0.90 hCV11461296 JAK3 endpt1 GG 125 1204 155 1153 0.0389 0.78 0.616 0.987 0.0111 C 0.02 G 0.98 hCV11461296 JAK3 endpt1 CG + CC 1 49 9 36 0.0255 0.09 0.012 0.749 0.0111 C 0.02 G 0.98 hCV11628130 rs2665802 GH1 endpt1 TT 18 254 33 212 0.0116 0.48 0.269 0.848 0.0640 T 0.42 A 0.58 hCV11628130 rs2665802 GH1 endpt1 TA + AA 113 1034 130 1001 0.2005 0.85 0.659 1.091 0.0640 T 0.42 A 0.58 hCV11642651 rs1800440 C2orf58 endpt1 CC 3 54 10 43 0.0467 0.27 0.074 0.981 0.0718 C 0.19 T 0.81 hCV11642651 rs1800440 C2orf58 endpt1 CT + TT 130 1237 155 1171 0.0651 0.8 0.636 1.014 0.0718 C 0.19 T 0.81 hCV11689916 endpt1 AA 35 369 56 340 0.0159 0.59 0.39 0.907 0.0899 A 0.48 T 0.52 hCV11689916 endpt1 AT + TT 97 863 102 816 0.5024 0.91 0.689 1.201 0.0899 A 0.48 T 0.52 hCV11697322 rs1926447 CPB2 endpt1 GG 59 655 93 616 0.0037 0.62 0.445 0.854 0.0540 A 0.29 G 0.71 hCV11697322 rs1926447 CPB2 endpt1 AG + AA 74 632 72 600 0.8558 0.97 0.702 1.342 0.0540 A 0.29 G 0.71 hCV11764545 rs4961 ADD1 endpt1 TT 2 52 7 41 0.0708 0.23 0.049 1.131 0.0921 T 0.18 G 0.82 hCV11764545 rs4961 ADD1 endpt1 TG + GG 131 1238 158 1176 0.0573 0.8 0.634 1.007 0.0921 T 0.18 G 0.82 hCV11955747 rs9901673 CD68 endpt1 CC 103 891 115 874 0.3731 0.89 0.679 1.156 0.0491 A 0.16 C 0.84 hCV11955747 rs9901673 CD68 endpt1 AC + AA 30 399 50 341 0.0058 0.53 0.336 0.832 0.0491 A 0.16 C 0.84 hCV11972326 rs5988 F13A1 endpt1 GG 13 69 8 80 0.2560 1.67 0.69 4.03 0.0738 G 0.24 C 0.76 hCV11972326 rs5988 F13A1 endpt1 GC + CC 120 1217 156 1133 0.0103 0.73 0.577 0.929 0.0738 G 0.24 C 0.76 hCV12020339 rs4531 DBH endpt1 GG 104 1095 145 1035 0.0043 0.69 0.538 0.891 0.0686 T 0.08 G 0.92 hCV12020339 rs4531 DBH endpt1 TG + TT 28 192 20 174 0.4707 1.24 0.696 2.193 0.0686 T 0.08 G 0.92 hCV12108469 CYP4A11 endpt1 AA 2 60 10 56 0.0353 0.2 0.043 0.893 0.0439 A 0.21 G 0.79 hCV12108469 CYP4A11 endpt1 AG + GG 128 1225 155 1148 0.0427 0.79 0.621 0.992 0.0439 A 0.21 G 0.79 hCV1243283 rs1716 ITGAE endpt1 AA 10 151 23 113 0.0037 0.33 0.158 0.7 0.0173 A 0.33 G 0.67 hCV1243283 rs1716 ITGAE endpt1 AG + GG 123 1138 142 1101 0.1788 0.85 0.666 1.079 0.0173 A 0.33 G 0.67 hCV1253630 rs2071307 ELN endpt1 GG 40 450 66 396 0.0030 0.55 0.373 0.818 0 0332 A 0.41 G 0.59 hCV1253630 rs2071307 ELN endpt1 AG + AA 92 839 96 813 0.6277 0.93 0.7 1.24 0.0332 A 0.41 G 0.59 hCV1345898 rs2230804 CHUK endpt1 CC 21 322 38 281 0.0134 0.51 0.299 0.869 0.0835 C 0.48 T 0.52 hCV1345898 rs2230804 CHUK endpt1 CT + TT 111 964 127 930 0.2025 0.85 0.657 1.093 0.0835 C 0.48 T 0.52 hCV1361979 rs25683 ACAT2 endpt1 GG 36 434 61 384 0.0037 0.54 0.36 0.821 0.0443 A 0.43 G 0.57 hCV1361979 rs25683 ACAT2 endpt1 AG + AA 97 851 104 820 0.4633 0.9 0.684 1.189 0.0443 A 0.43 G 0.57 hCV1375141 rs1881420 ALK endpt1 CC 10 69 6 61 0.4852 1.43 0.521 3.947 0.0936 C 0.21 T 0.79 hCV1375141 rs1881420 ALK endpt1 CT 33 421 60 399 0.0053 0.55 0.357 0.835 0.0936 C 0.21 T 0.79 hCV1375141 rs1881420 ALK endpt1 TT 90 799 99 757 0.3071 0.86 0.648 1.146 0.0936 C 0.21 T 0.79 hCV1552894 rs434473 ALOX12 endpt1 GG 16 212 43 222 0.0028 0.42 0.234 0.739 0.0162 G 0.42 A 0.58 hCV1552894 rs434473 ALOX12 endpt1 GA + AA 116 1073 122 990 0.3177 0.88 0.681 1.133 0.0162 G 0.42 A 0.58 hCV1552900 rs1126667 ALOX12 endpt1 AA 16 212 43 223 0.0030 0.42 0.236 0.744 0.0159 A 0.42 G 0.58 hCV1552900 rs1126667 ALOX12 endpt1 AG + GG 117 1076 122 991 0.3456 0.89 0.687 1.141 0.0159 A 0.42 G 0.58 hCV15746640 rs41271951 CTSS endpt1 AA 109 1096 150 1021 0.0032 0.69 0.539 0.883 0.0177 G 0.08 A 0.92 hCV15746640 rs41271951 CTSS endpt1 GA + GG 24 194 15 193 0.1717 1.57 0.823 2.99 0.0177 G 0.08 A 0.92 hCV15758290 rs6716834 LRP2 endpt1 AA 53 635 87 563 0.0030 0.6 0.434 0.843 0.0441 G 0.30 A 0.70 hCV15758290 rs6716834 LRP2 endpt1 GA + GG 75 648 78 646 0.8294 0.97 0.703 1.326 0.0441 G 0.30 A 0.70 hCV15760070 rs2308911 HLA-DPA1 endpt1 TT 7 31 1 38 0.0713 6.88 0.846 5.6019 0.0073 T 0.17 A 0.83 hCV15760070 rs2308911 HLA-DPA1 endpt1 TA + AA 126 1258 164 1179 0.0090 0.73 0.582 0.926 0.0073 T 0.17 A 0.83 hCV15851335 rs17610395 CPT1A endpt1 CC 111 1123 147 1039 0.0073 0.71 0.558 0.913 0.0891 T 0.07 C 0.93 hCV15851335 rs17610395 CPT1A endpt1 TC + TT 21 164 17 176 0.4412 1.29 0.678 2.437 0.0891 T 0.07 C 0.93 hCV15851779 rs2230009 WRN endpt1 AA 0 6 2 4 0.9977 0 0 . 0.0624 A 0.06 G 0.94 hCV15851779 rs2230009 WRN endpt1 AG 20 132 14 129 0.3772 1.36 0.687 2.693 0.0624 A 0.06 G 0.94 hCV15851779 rs2230009 WRN endpt1 GG 113 1150 149 1082 0.0103 0.73 0.569 0.927 0.0624 A 0.06 G 0.94 hCV15876011 rs2228541 SERPINA6 endpt1 GG 35 261 24 239 0.3001 1.32 0.783 2.212 0.0268 G 0.45 T 0.55 hCV15876011 rs2228541 SERPINA6 endpt1 GT + TT 96 991 137 951 0.0048 0.69 0.529 0.892 0.0268 G 0.45 T 0.55 hCV15954277 rs2236379 PRKCQ endpt1 AA 13 103 3 92 0.0411 3.7 1.054 12.989 0.0042 A 0.26 G 0.74 hCV15954277 rs2236379 PRKCQ endpt1 AG + GG 120 1188 162 1126 0.0054 0.72 0.565 0.906 0.0042 A 0.26 G 0.74 hCV15955388 rs2227376 F2RL3 endpt1 CC 132 1247 157 1173 0.0594 0.8 0.635 1.009 0.0435 T 0.02 C 0.98 hCV15955388 rs2227376 F2RL3 endpt1 TC + TT 1 42 8 42 0.0629 0.14 0.017 1.112 0.0435 T 0.02 C 0.98 hCV15963535 rs2228591 NCOA2 endpt1 CC 124 1155 142 1087 0.1293 0.83 0.652 1.056 0.0412 G 0.05 C 0.95 hCV15963535 rs2228591 NCOA2 endpt1 GC + GG 8 132 23 130 0.0128 0.36 0.161 0.805 0.0412 G 0.05 C 0.95 hCV1600754 rs17288671 CXCL9 endpt1 CC 34 396 51 324 0.0099 0.56 0.366 0.872 0.0869 T 0.46 C 0.54 hCV1600754 rs17288671 CXCL9 endpt1 TC + TT 99 892 114 893 0.3365 0.88 0.669 1.147 0.0869 T 0.46 C 0.54 hCV1603697 rs2229475 HSPG2 endpt1 CC 122 1141 142 1083 0.1196 0.83 0.648 1.051 0.0985 T 0.06 C 0.94 hCV1603697 rs2229475 HSPG2 endpt1 TC + TT 11 148 23 132 0.0253 0.44 0.215 0.904 0.0985 T 0.06 C 0.94 hCV16044337 rs2569491 KLK14 endpt1 AA 7 127 26 114 0.0012 0.25 0.11 0.582 0.0028 A 0.31 G 0.69 hCV16044337 rs2569491 KLK14 endpt1 AG + GG 126 1157 138 1095 0.2664 0.87 0.685 1.11 0.0028 A 0.31 G 0.69 hCV16047108 rs2244008 LAMA2 endpt1 AA 104 1148 145 1062 0.0025 0.68 0.527 0.872 0.0174 G 0.06 A 0.94 hCV16047108 rs2244008 LAMA2 endpt1 GA + GG 28 140 20 151 0.2238 1.43 0.804 2.537 0.0174 G 0.06 A 0.94 hCV16172339 rs2229489 HSPG2 endpt1 AA 121 1140 141 1081 0.1176 0.82 0.646 1.05 0.0974 T 0.06 A 0.94 hCV16172339 rs2229489 HSPG2 endpt1 TA + TT 11 147 23 131 0.0251 0.44 0.214 0.903 0.0974 T 0.06 A 0.94 hCV16173091 rs2241883 FABP1 endpt1 CC 18 126 10 136 0.1086 1.88 0.869 4.079 0.0148 C 0.32 T 0.68 hCV16173091 rs2241883 FABP1 endpt1 CT + TT 115 1164 155 1080 0.0041 0.7 0.552 0.894 0.0148 C 0.32 T 0.68 hCV16179493 rs2108622 CYP4F2 endpt1 CC 54 613 90 574 0.0015 0.58 0.413 0.811 0.0241 T 0.31 C 0.69 hCV16179493 rs2108622 CYP4F2 endpt1 TC + TT 77 670 75 640 0.9145 0.98 0.715 1.351 0.0241 T 0.31 C 0.69 hCV16179628 rs2273697 ABCC2 endpt1 AA 1 68 4 28 0.0562 0.12 0.013 1.058 0.475 A 0.20 G 0.80 hCV16179628 rs2273697 ABCC2 endpt1 AG + GG 132 1220 161 1189 0.0668 0.81 0.641 1.015 0.0472 A 0.20 G 0.80 hCV16182835 rs2274736 PTPN21 endpt1 AA 70 555 62 511 0.8609 1.03 0.733 1.451 0.0411 G 0.34 A 0.66 hCV16182835 rs2274736 PTPN21 endpt1 GA + GG 62 703 98 684 0.0053 0.64 0.463 0.874 0.0411 G 0.34 A 0.66 hCV16192174 rs2305948 KDR endpt1 GG 96 1043 134 984 0.0052 0.69 0.53 0.895 0.0847 A 0.10 G 0.90 hCV16192174 rs2305948 KDR endpt1 AG + AA 37 248 31 232 0.6835 1.1 0.685 1.78 0.0847 A 0.10 G 0.90 hCV1647371 rs3025000 VEGFA endpt1 CC 57 600 88 529 0.0026 0.6 0.429 0.835 0.0251 T 0.33 C 0.67 hCV1647371 rs3025000 VEGFA endpt1 TC + TT 75 662 73 664 0.9194 1.02 0.737 1.403 0.0251 T 0.33 C 0.67 hCV1741111 rs1764391 C1orf2l2 endpt1 TT 1 114 6 97 0.2976 1.68 0.632 4.486 0.0931 T 0.30 C 0.70 hCVl741111 rs1764391 C1orf212 endpt1 TC + CC 121 1174 159 1118 0.0109 0.74 0.581 0.932 0.0931 T 0.30 C 0.70 hCV1770462 rs12731981 MPL endpt1 GG 114 1204 153 1141 0.0070 0.72 0.562 0.913 0.0818 A 0.03 G 0.97 hCV1770462 rs12731981 MPL endpt1 AG + AA 18 82 12 76 0.3614 1.41 0.677 2.918 0.0818 A 0.03 G 0.97 hCV1843175 rs3745535 KLK10 endpt1 CC 57 528 59 538 0.9494 0.99 0.687 1.422 0.0787 A 0.36 C 0.64 hCVl843175 rs3745535 KLK10 endpt1 AC + AA 75 754 106 675 0.0040 0.65 0.482 0.87 0.0787 A 0.36 C 0.64 hCV2038 rs4673 CYBA endpt1 GG 44 563 76 520 0.0018 0.55 0.382 0 803 0.0216 A 0.34 G 0.66 hCV2038 rs4673 CYBA endpt1 AG + AA 89 728 89 697 0.7717 0.96 0.714 1.284 0.0216 A 0.34 G 0.66 hCV2143205 rs9666607 CD44 endpt1 AA 16 125 9 119 0.2301 1.65 0.729 3.732 0.0524 A 0.32 C 0.68 hCV2143205 rs9666607 CD44 endpt1 AG + GG 117 1167 156 1099 0.0072 0.72 0.567 0.915 0.0524 A 0.32 G 0.68 hCV22271999 rs2305948 KDR endpt1 CC 96 1041 133 981 0.0060 0.69 0.532 0.9 0.0944 T 0.10 C 0.90 hCV22271999 rs2305948 KDR endpt1 TC + TT 37 248 31 230 0.7100 1.09 0.679 1.764 0.0944 T 0.10 C 0.90 hCV22274761 rs11575194 IGFBP5 endpt1 GG 126 1175 149 1113 0.0831 0.81 0.64 1.028 0.0849 A 0.04 G 0.96 hCV22274761 rs11575194 IGFBP5 endpt1 AG + AA 6 108 16 100 0.0333 0.36 0.141 0.923 0.0849 A 0.04 G 0.96 hCV22275550 rs6836335 SPON2 endpt1 CC 3 15 1 26 0.2235 4.08 0.424 39.314 0.0946 C 0.12 T 0.88 hCV22275550 rs6836335 SPON2 endpt1 CT + TT 129 1270 164 1189 0.0139 0.75 0.594 0.943 0.0946 C 0.12 T 0.88 hCV2230606 rs13268 FBLN1 endpt1 AA 124 1224 161 1153 0.0109 0.74 0.584 0.932 0.0281 G 0.02 A 0.98 hCV2230606 rs13268 FBLN1 endpt1 GA + GG 9 62 3 63 0.1073 2.93 0.792 10.814 0.0281 G 0.02 A 0.98 hCV2276802 rs381418 GBA endpt1 AA 33 354 54 313 0.0088 0.56 0.364 0.865 0.0820 C 0.37 A 0.63 hCV2276802 rs381418 GBA endpt1 CA + CC 100 935 110 903 0.3623 0.88 0.673 1.156 0.0820 C 0.37 A 0.63 hCV2310409 45474794- APOA4 endpt1 TT 76 825 107 756 0.0061 0.66 0.494 0.889 0.1000 A 0.20 T 0.80 rs6 hCV2310409 45474794- APOA4 endpt1 AT + AA 56 459 56 450 0.9347 0.98 0.68 1.426 0.1000 A 0.20 T 0.80 rs6 hCV2485037 rs4904448 SPATA7 endpt1 AA 31 228 23 219 0.4154 1.25 0.73 2.146 0.0581 A 0.43 G 0.57 hCV2485037 rs4904448 SPATA7 endpt1 AG + GG 101 1032 137 965 0.0082 0.71 0.547 0.914 0.0581 A 0.43 G 0.57 hCV2503034 rs1132356 BAIAP3 endpt1 AA 0 16 3 4 0.9978 0 0 . 0.0411 A 0.11 C 0.89 hCV2503034 rs1132356 BAIAP3 endpt1 AC 34 258 35 219 0.3764 0.81 0.504 1.296 0.0411 A 0.11 C 0.89 hCV2503034 rs1132356 BAIAP3 endpt1 CC 97 1010 126 985 0.0498 0.77 0.589 1 0.0411 A 0.11 C 0.89 hCV2531086 rs10406069 CD22 endpt1 AA 7 52 2 47 0.1378 3.29 0.682 15.892 0.0460 A 0.21 G 0.79 hCV2531086 rs10406069 CD22 endpt1 AG + GG 124 1236 163 1167 0.0081 0.73 0.577 0.921 0.0460 A 0.21 G 0.79 hCV2536595 rs704 VTN endpt1 GG 44 351 34 381 0.1617 1.38 0.88 2.154 0.0027 A 0.47 G 0.53 hCV2536595 rs704 VTN endpt1 AG + AA 89 940 131 837 0.0005 0.62 0.475 0.814 0.0027 A 0.47 G 0.53 hCV25472345 rs4900072 C14orf159 endpt1 TT 8 154 29 160 0.0036 0.31 0.143 0.683 0.0075 T 0.34 C 0.66 hCV25472345 rs4900072 C14orf159 endpt1 TC + CC 124 1108 130 1029 0.3416 0.89 0.694 1.135 0.0075 T 0.34 C 0.66 hCV25472673 rs1805081 NPC1 endpt1 TT 59 484 47 455 0.4153 1.17 0.799 1.72 0.0080 C 0.39 T 0.61 hCV25472673 rs1805081 NPC1 endpt1 CT + CC 74 803 117 761 0.0010 0.61 0.459 0.822 0.0080 C 0.39 T 0.61 hCV25473098 rs2241883 FABP1 endpt1 GG 18 124 11 137 0.1440 1.75 0.826 3.704 0.0227 G 0.31 A 0.69 hCV25473098 rs2241883 FABP1 endpt1 GA + AA 115 1165 152 1071 0.0055 0.71 0.557 0.904 0.0227 G 0.31 A 0.69 hCV25474101 rs41554412 MICA endpt1 CC 7 25 2 32 0.0951 3.81 0.792 18.358 0.0195 C 0.15 T 0.85 hCV25474101 rs41554412 MICA endpt1 CT + TT 126 1266 163 1184 0.0094 0.73 0.582 0.927 0.0195 C 0.15 T 0.85 hCV25591528 CD163 endpt1 GG 114 994 128 956 0.2637 0.87 0.673 1.115 0.0417 A 0.12 G 0.88 hCV25591528 CD163 endpt1 AG + AA 19 296 37 262 0.0065 0.46 0.267 0.807 0.0417 A 0.12 G 0.88 hCV25596880 rs4647297 CASP2 endpt1 CC 2 3 0 6 0.9977 1E+08 0 . 0.0713 C 0.06 G 0.94 hCV25596880 rs4647297 CASP2 endpt1 CG 12 136 12 137 0.9890 0.99 0.447 2.214 0.0713 C 0.06 G 0.94 hCV25596880 rs4647297 CASP2 endpt1 GG 118 1150 153 1072 0.0107 0.73 0.575 0.93 0.0713 C 0.06 G 0.94 hCV25598594 rs41274768 CR1 endpt1 GG 132 1226 154 1167 0.1016 0.82 0.653 1.039 0.0028 A 0.02 G 0.98 hCV25598594 rs41274768 CR1 endpt1 AG + AA 1 65 11 50 0.0150 0.08 0.01 0.01 0.0028 A 0.02 G 0.98 hCV25603879 rs11542844 SCNN1A endpt1 CC 122 1200 160 1126 0.0082 0.73 0.575 0.921 0.0527 T 0.03 C 0.97 hCV25603879 rs11542844 SCNN1A endpt1 TC + TT 11 89 5 85 0.2080 1.97 0.685 5.68 0.0527 T 0.03 C 0.97 hCV25605897 rs11568563 SLCO1A2 endpt1 TT 126 1140 144 1088 0.1708 0.85 0.666 1.075 0.0166 G 0.06 T 0.94 hCV25605897 rs11568563 SLCO1A2 endpt1 GT + GG 7 150 20 126 0.0065 0.3 0.128 0.716 0.0166 G 0.06 T 0.94 hCV25607193 FLNB endpt1 TT 127 1258 164 1191 0.0129 0.75 0.591 0.94 0.0477 C 0.01 T 0.99 hCV25607193 FLNB endpt1 CT + CC 6 33 1 27 0.1685 4.42 0.533 3.6753 0.0477 C 0.01 T 0.99 hCV25608818 SLC10A2 endpt1 GG 126 1258 162 1176 0.0110 0.74 0.586 0.933 0.0206 A 0.01 G 0.99 hCV25608818 SLC10A2 endpt1 AG + AA 7 32 2 40 0.0832 4.01 0.833 1.9312 0.0206 A 0.01 G 0.99 hCV25610470 rs34075341 C9orf47 endpt1 GG 128 1182 151 1128 0.0946 0.82 0.646 1.035 0.0431 A 0.04 G 0.96 hCV25610470 rs34075341 C9orf47 endpt1 AG + AA 4 103 13 87 0.0235 0.27 0.089 0.84 0.0431 A 0.04 C 0.96 hCV25610774 rs8176748 endpt1 TT 5 57 2 67 0.2456 2.64 0.512 1.3644 0.0989 T 0.23 C 0.77 hCV25610774 rs8176748 endpt1 TC + CC 127 1231 163 1150 0.0116 0.74 0.588 0.935 0.0989 T 0.23 C 0.77 hCV25610819 rs8176740 endpt1 TT 5 58 2 70 0.2297 2.73 0.53 14.102 0.0925 T 0.23 A 0.77 hCV25610819 rs8176740 endpt1 TA + AA 128 1225 163 1139 0.0122 0.74 0.59 0.937 0.0925 T 0.23 A 0.77 hCV25614016 rs7607759 CAPN10 endpt1 AA 87 915 130 840 0.0010 0.63 0.482 0.83 0.0072 G 0.16 A 0.84 hCV25614016 rs7607759 CAPN10 endpt1 GA + GG 46 374 35 374 0.2727 1.28 0.824 1.985 0.0072 G 0.16 A 0.84 hCV25617571 rs2232580 LBP endpt1 CC 117 1090 132 1052 0.2572 0.87 0.675 1.111 0.0208 T 0.08 C 0.92 hCV25617571 rs2232580 LBP endpt1 TC + TT 16 200 33 165 0.0037 0.41 0.227 0.751 0.0208 T 0.08 C 0.92 hCV25623265 rs3746638 SIGLEC1 endpt1 GG 14 288 40 279 0.0008 0.35 0.193 0.65 0.0039 G 0.48 A 0.52 hCV25623265 rs3746638 SIGLEC1 endpt1 GA + AA 118 1000 125 936 0.3626 0.89 0.692 1.144 0.0039 G 0.48 A 0.52 hCV25629396 rs3729823 MYH7 endpt1 GG 125 1260 163 1166 0.0064 0.72 0.573 0.913 0.0011 C 0.01 G 0.99 hCV25629396 rs3729823 MYH7 endpt1 CG + CC 7 26 1 48 0.0266 10.7 1.317 87.094 0.0011 C 0.01 G 0.99 hCV25629476 rs2427284 LAMA5 endpt1 GG 111 1158 150 1095 0.0071 0.71 0.558 0.912 0.0602 A 0.05 G 0.95 hCV25629476 rs2427284 LAMA5 endpt1 AG + AA 22 131 14 121 0.3104 1.41 0.724 2.765 0.0602 A 0.05 G 0.95 hCV25629492 rs944895 LAMA5 endpt1 AA 66 511 71 513 0.6944 0.94 0.669 1.307 0.0916 G 0.36 A 0.64 hCV25629492 rs944895 LAMA5 endpt1 GA + GG 64 773 94 696 0.0043 0.63 0.458 0.865 0.0916 G 0.36 A 0.64 hCV25629888 rs11539441 TIMP2 endpt1 GG 7 30 3 34 0.1786 2.53 0.654 9.788 0.0742 G 0.17 C 0.83 hCV25629888 rs11539441 TIMP2 endpt1 GC + CC 125 1261 161 1184 0.0120 0.74 0.587 0.936 0.0742 G 0.17 C 0.83 hCV25652744 rs1127525 USP21 endpt1 AA 1 0 0 4 1.0000 4E+12 0 . 0.0261 A 0.05 C 0.95 hCV25652744 rs1127525 USP21 endpt1 AC 5 113 15 107 0.0373 0.34 0.124 0.939 0.0261 A 0.05 C 0.95 hCV25652744 rs1127525 USP21 endpt1 CC 127 1153 145 1082 0.1210 0.83 0.653 1.051 0.0261 A 0.05 C 0.95 hCV1026586 rs673548 APOB endpt1 GA + GG 127 1203 163 1147 0.0160 0.75 0.60 0.95 0.0780 A 0.22 G 0.78 hCV1026586 rs673548 APOB endpt1 AA 9 59 4 58 0.2000 2.15 0.66 6.97 0.0780 A 0.22 G 0.78 hCV11466848 rs1805419 BAX endpt1 AG + AA 53 620 93 563 0.0003 0.54 0.38 0.75 0.0020 A 0.28 G 0.72 hCV11466848 rs1805419 BAX endpt1 GG 83 645 74 643 0.5200 1.11 0.81 1.52 0.0020 A 0.28 G 0.72 hCV11513719 rs2967605 ELAVL1 endpt1 TC + TT 40 425 67 372 0.0019 0.54 0.36 0.80 0.0180 C 0.82 T 0.18 hCV11513719 rs2967605 ELAVL1 endpt1 CC 95 832 99 829 0.7800 0.96 0.73 1.27 0.0180 C 0.82 T 0.18 hCV1323634 rs287475 endpt1 TC + TT 106 1034 149 980 0.0031 0.69 0.54 0.88 0.0074 C 0.43 T 0.57 hCV1323634 rs287475 endpt1 CC 30 229 18 225 0.1000 1.63 0.91 2.93 0.0074 C 0.43 T 0.57 hCV1323669 rs287354 endpt1 GA + GG 104 1023 144 968 0.0048 0.70 0.54 0.89 0.0190 A 0.44 G 0.56 hCV1323669 rs287354 endpt1 AA 32 244 22 239 0.2100 1.42 0.82 2.44 0.0190 A 0.44 G 0.56 hCV1729928 rs10509384 KCNMA1 endpt1 AG + AA 117 1119 153 1043 0.0096 0.73 0.57 0.93 0.0880 A 0.66 G 0.34 hCV1729928 rs10509384 KCNMA1 endpt1 GG 18 142 14 158 0.3600 1.39 0.69 2.79 0.0880 A 0.66 G 0.34 hCV1948599 rs504527 CSMD2 endpt1 CA + CC 92 989 129 920 0.0041 0.68 0.52 0.88 0.0320 A 0.49 C 0.51 hCV1948599 rs504527 CSMD2 endpt1 AA 44 275 38 283 0.4600 1.18 0.76 1.82 0.0320 A 0.49 C 0.51 hCV2554615 rs2522057 LOC441108 endpt1 CG + CC 107 1046 146 998 0.0098 0.72 0.56 0.92 0.0580 C 0.58 G 0.42 hCV2554615 rs2522057 LOC441108 endpt1 GG 29 216 20 208 0.3900 1.28 0.73 2.27 0.0580 C 0.58 G 0.42 hCV2554721 rs7315519 RPH3A endpt1 AG + AA 84 911 130 844 0.0005 0.62 0.47 0.81 0.0015 A 0.46 G 0.54 hCV2554721 rs7315519 RPH3A endpt1 GG 52 355 37 361 0.1200 1.39 0.91 2.12 0.0015 A 0.46 G 0.54 hCV260164 rs6754295 endpt1 TG + TT 127 1195 163 1138 0.0160 0.75 0.60 0.95 0.0720 G 0.24 T 0.76 hCV260164 rs6754295 endpt1 GG 9 68 4 68 0.1900 2.19 0.67 7.10 0.0720 G 0.24 T 0.76 hCV2762168 rs3939286 endpt1 TC + TT 62 592 91 531 0.0052 0.63 0.46 0.87 0.0600 C 0.74 T 0.26 hCV2762168 rs3939286 endpt1 CC 74 673 76 673 0.8700 0.97 0.71 1.34 0.0600 C 0.74 T 0.26 hCV2781953 rs6021931 endpt1 GT + GG 127 1214 161 1158 0.0220 0.76 0.6 0.96 0.0870 G 0.81 T 0.19 hCV2781953 rs6021931 endpt1 TT 9 49 4 46 0.2000 2.15 0.66 7.02 0.0670 G 0.81 T 0.19 hCV29011391 rs7557067 endpt1 AG + AA 126 1191 163 1139 0.0150 0.75 0.59 0.95 0.0790 A 0.76 G 0.24 hCV29011391 rs7557067 endpt1 GG 9 69 4 67 0.2100 2.13 0.66 6.91 0.0790 A 0.76 C 0.24 hCV29l35108 rs6743779 KLF7 endpt1 CA + CC 61 661 103 633 0.0009 0.58 0.43 0.80 0.0076 A 0.69 C 0.31 hCV29135108 rs6743779 KLF7 endpt1 AA 74 601 64 572 0.5900 1.10 0.78 1.53 0.0076 A 0.69 C 0.31 hCV30264691 rs10508518 CUBN endpt1 TG + TT 121 1148 157 1087 0.0140 0.74 0.59 0.94 0.0910 C 0.30 T 0.70 hCV30264691 rs10508518 CUBN endpt1 GG 15 111 10 116 0.3000 1.53 0.69 3.41 0.0910 G 0.30 T 0.70 hCV30606396 rs10438978 endpt1 TC + TT 40 428 62 375 0.0074 0.58 0.39 0.86 0.0650 C 0.82 T 0.18 hCV30606396 rs10438978 endpt1 CC 96 834 105 830 0.5400 0.92 0.70 1.21 0.0650 C 0.82 T 0.18 hCV31237961 rs11950562 SLC22A4 endpt1 AC + AA 101 986 143 936 0.0046 0.69 0.54 0.89 0.0260 A 0.53 C 0.47 hCV31237961 rs11950562 SLC22A4 endpt1 CC 35 279 24 268 0.3100 1.31 0.78 2.2 0.0260 A 0.53 C 0.47 hCV3168675 rs469930 endpt1 GA + GG 77 766 109 709 0.0066 0.67 0.5 0.89 0.0790 A 0.64 G 0.36 hCV3168675 rs469930 endpt1 AA 59 499 58 495 0.9500 1.01 0.7 1.45 0.0790 A 0.64 G 0.36 hCV3170445 rs272893 SLC22A4 endpt1 TC + TT 81 779 121 732 0.0032 0.65 0.49 0.87 0.0260 C 0.61 T 0.39 hCV3170445 rs272893 SLC22A4 endpt1 CC 55 487 46 474 0.5400 1.13 0.76 1.67 0.0260 C 0.61 T 0.39 hCV3170459 rs1050152 SLC22A4 endpt1 CT + CC 105 1038 145 989 0.0079 0.71 0.55 0.91 0.0550 C 0.58 T 0.42 hCV3170459 rs1050152 SLC22A4 endpt1 TT 31 223 22 217 0.4200 1.25 0.72 2.16 0.0550 C 0.58 T 0.42 hCV3242919 rs486394 endpt1 AC + AA 120 1158 159 1110 0.0110 0.74 0.58 0.93 0.0490 A 0.71 C 0.29 hCV3242919 rs486394 endpt1 CC 16 104 8 96 0.1800 1.78 0.76 4.17 0.0490 A 0.71 C 0.29 hCV3242952 rs2000571 endpt1 AG + AA 42 464 74 448 0.0035 0.57 0.39 0.83 0.0320 A 0.21 G 0.79 hCV3242952 rs2000571 endpt1 GG 94 799 93 757 0.7700 0.96 0.72 1.28 0.0320 A 0.21 G 0.79 hCV610861 rs636887 endpt1 TC + TT 108 1017 146 973 0.0110 0.72 0.56 0.93 0.0900 C 0.43 T 0.57 hCV610861 rs636887 endpt1 CC 28 247 21 233 0.4800 1.23 0.7 2.16 0.0900 C 0.43 T 0.57 hCV7501549 rs1467412 ATP9A endpt1 CT + CC 93 947 132 903 0.0063 0.69 0.53 0.9 0.0620 C 0.50 T 0.50 hCV7501549 rs1467412 ATP9A endpt1 TT 43 319 35 303 0.5800 1.13 0.73 1.77 0.0620 C 0.50 T 0.50 hCV7537517 rs1501908 endpt1 CG + CC 117 1087 156 1041 0.0100 0.73 0.58 0.93 0.0320 C 0.64 G 0.36 hCV7537517 rs1501908 endpt1 GG 19 175 10 165 0.1500 1.75 0.82 3.77 0.0320 C 0.64 G 0.36 hCV7910239 rs1541296 FVT1 endpt1 AG + AA 118 1111 152 1041 0.0140 0.74 0.58 0.94 0.0850 A 0.66 G 0.34 hCV7910239 rs1541296 FVT1 endpt1 GG 18 147 14 163 0.3200 1.43 0.71 2.87 0.0850 A 0.66 G 0.34 hCV8420416 rs719909 PANK1 endpt1 CT + CC 131 1236 165 1164 0.0200 0.76 0.61 0.96 0.0770 C 0.84 T 0.16 hCV8420416 rs719909 PANK1 endpt1 TT 5 26 2 41 0.1500 3.29 0.64 16.97 0.0770 C 0.84 T 0.16 hCV8785827 rs992969 IL33 endpt1 AG + AA 61 591 91 527 0.0038 0.62 0.45 0.86 0.0430 A 0.26 G 0.74 hCV8785827 rs992969 IL33 endpt1 GG 75 675 76 677 0.9400 0.99 0.72 1.36 0.0430 A 0.26 G 0.74 hCV8892418 rs901746 ACP2 endpt1 GA + GG 53 630 87 593 0.0024 0.59 0.42 0.83 0.0220 A 0.71 G 0.29 hCV8892418 rs901746 ACP2 endpt1 AA 83 632 80 613 0.9600 1.01 0.74 1.37 0 0220 A 0.71 G 0.29 hCV11678789 rs7219148 endpt1 TG + GG 111 918 116 905 0.6900 0.95 0.73 1.23 0 0058 G 0.48 T 0.52 hCV11678789 rs7219148 endpt1 TT 25 348 51 301 0.0007 0.44 0.27 0.71 0.0058 G 0.48 T 0.52 hCV11864162 rs1167998 DOCK7 endpt1 AC + CC 84 692 90 701 0.7400 0.95 0.71 1.28 0.0660 A 0.66 C 0.34 hCV11864162 rs1167998 DOCK7 endpt1 AA 52 570 76 504 0.0074 0.62 0.43 0.88 0.0660 A 0.66 C 0.34 hCV1239369 rs275982 endpt1 CA + AA 88 713 90 698 0.7300 0.95 0.71 1.27 0.0510 A 0.35 C 0.65 hCV1239369 rs275982 endpt1 CC 48 552 77 508 0.0051 0.6 0.42 0.86 0.0510 A 0.35 C 0.65 hCV1488444 rs10164405 endpt1 TG + GG 129 1159 148 1096 0.1400 0.84 0.66 1.06 0.0910 G 0.71 T 0.29 hCV1488444 rs10164405 endpt1 TT 7 103 19 107 0.0240 0.37 0.15 0.88 0.0910 G 0.71 T 0.29 hCV1489995 rs4013819 LOC392281 endpt1 GC + CC 120 1076 133 1035 0.2900 0.88 0.68 1.12 0.0440 C 0.63 G 0.37 hCV1489995 rs4013819 LOC392281 endpt1 GG 16 185 34 170 0.0090 0.45 0.25 0.82 0.0440 C 0.63 G 0.37 hCV15870728 rs2943245 C10orf64 endpt1 CT + TT 106 922 112 868 0.4000 0.89 0.68 1.16 0.0890 C 0.53 T 0.47 hCV15870728 rs2943245 C10orf64 endpt1 CC 30 340 55 338 0.0130 0.57 0.36 0.89 0.0890 C 0.53 T 0.47 hCV1802755 rS7764347 RFXDC1 endpt1 CT + TT 134 1216 158 1165 0.0920 0.82 0.65 1.03 0.0880 C 0.18 T 0.82 hCV1802755 rs7764347 RFXDC1 endpt1 CC 2 47 9 40 0.0470 0.21 0.05 0.98 0.0880 C 0.18 T 0.82 hCV2557331 rs233716 RPH3A endpt1 CT + TT 118 1029 133 1001 0.2600 0.87 0.68 1.11 0.0830 C 0.42 T 0.58 hCV2557331 rs233716 RPH3A endpt1 CC 18 235 33 203 0.0190 0.5 0.28 0.89 0.0830 C 0.42 T 0.58 hCV2632070 rs714052 BAZ1B endpt1 AG + GG 40 289 30 263 0.4300 1.21 0.75 1.94 0.0400 A 0.88 G 0.12 hCV2632070 rs714052 BAZ1B endpt1 AA 96 974 137 940 0.0050 0.69 0.53 0.89 0.0400 A 0.88 G 0.12 hCV2632498 rs3812316 MLXIPL endpt1 CG + GG 40 297 33 277 0.6200 1.12 0.71 1.78 0.0780 C 0.87 G 0.13 hCV2632498 rs3812316 MLXIPL endpt1 CC 96 969 134 929 0.0076 0.7 0.54 0.91 0.0780 C 0.87 G 0.13 hCV2632544 rs17145738 endpt1 CT + TT 41 283 31 271 0.3400 1.25 0.79 2.00 0.0230 C 0.88 T 0.12 hCV2632544 rs17145738 endpt1 CC 95 983 136 936 0.0037 0.68 0.52 0.88 0.0230 C 0.88 T 0.12 hCV28974083 rs8032553 C15orf42 endpt1 GA + AA 105 902 116 899 0.4500 0.90 0.69 1.18 0.0510 A 0.48 G 0.52 hCV28974083 rs8032553 C15orf42 endpt1 GG 31 360 51 306 0.0067 0.54 0.35 0.84 0.0510 A 0.48 G 0.52 hCV31145250 rs10889353 DOCK7 endpt1 AC + CC 84 685 87 687 0.8600 0.97 0.72 1.31 0.0450 A 0.66 C 0.34 hCV31145250 rs10889353 DOCK7 endpt1 AA 52 575 79 519 0.0053 0.61 0.43 0.86 0.0450 A 0.66 C 0.34 hCV31528409 rs7635061 endpt1 AG + GG 74 606 74 587 0.8400 0.97 0.7 1.34 0.0850 A 0.71 G 0.29 hCV31528409 rs7635061 endpt1 AA 62 659 92 619 0.0085 0.65 0.47 0.9 0.0850 A 0.71 G 0.29 hCV31954792 rs6477693 C9orf4 endpt1 CA + AA 129 1163 148 1103 0.1400 0.84 0.66 1.06 0.0830 A 0.72 C 0.28 hCV31954792 rs6477693 C9orf4 endpt1 CC 7 103 19 101 0.0280 0.38 0.16 0.9 0.0830 A 0.72 C 0.28 hCV461035 rs7746448 endpt1 TC + CC 89 785 99 796 0.5300 0.91 0.69 1.21 0.0970 C 0.40 T 0.60 hCV461035 rs7746448 endpt1 TT 47 481 68 410 0.0094 0.61 0.42 0.89 0.0970 C 0.40 T 0.60 hCV601961 rs568654 ZNF568 endpt1 AG + GG 118 1072 135 1040 0.2200 0.86 0.67 1.10 0.0950 A 0.38 G 0.62 hCV601961 rs568654 ZNF568 endpt1 AA 18 190 32 166 0.0210 0.51 0.28 0.90 0.0950 A 0.38 G 0.62 hCV8785824 rs1412426 endpt1 AC + CC 128 1137 142 1080 0.2300 0.86 0.68 1.1 0.0200 A 0.33 C 0.67 hCV8785824 rs1412426 endpt1 AA 8 127 25 122 0.0060 0.33 0.15 0.73 0.0200 A 0.33 C 0.67 hCV9581635 rs1748195 DOCK7 endpt1 CG + GG 84 687 88 694 0.8500 0.97 0.72 1.31 0.0440 C 0.66 G 0.34 hCV9581635 rs1748195 DOCK7 endpt1 CC 52 575 78 511 0.0051 0.61 0.43 0.86 0.0440 C 0.66 G 0.34 hCV9588862 rs995000 DOCK7 endpt1 CT + TT 84 688 88 683 0.7600 0.95 0.71 1.29 0.0570 C 0.66 T 0.34 hCV9588862 rs995000 DOCK7 endpt1 CC 52 577 79 523 0.0057 0.61 0.43 0.87 0.0570 C 0.66 T 0.34 hDV76976592 rs4149274 ABCA1 endpt1 GA + AA 84 705 83 669 0.8100 0.96 0.71 1.31 0.0540 A 0.34 G 0.66 hDV76976592 rs4149274 ABCA1 endpt1 GG 52 557 84 537 0.0057 0.61 0.43 0.87 0.0540 A 0.34 G 0.66 hCV11568668 rs1317538 KCNQ5 endpt1 AA 43 324 49 277 0.2300 0.78 0.52 1.17 0.0343 A 0.49 G 0.51 hCV11568668 rs1317538 KCNQ5 endpt1 AG 70 607 67 603 0.9100 1.02 0.73 1.43 0.0343 A 0.49 G 0.51 hCV11568668 rs1317538 KCNQ5 endpt1 GG 23 336 50 328 0.0028 0.47 0.29 0.77 0.0343 A 0.49 G 0.51 hCV2221541 rs739161 endpt1 CC 7 121 17 80 0.0066 0.30 0.12 0.71 0.0367 C 0.29 T 0.71 hCV2221541 rs739161 endpt1 TC 55 492 60 535 0.9400 0.99 0.68 1.42 0.0367 C 0.29 T 0.71 hCV2221541 rs739161 endpt1 TT 74 649 90 591 0.0910 0.77 0.56 1.04 0.0367 C 0.29 T 0.71 hCV601962 rs544543 ZNF568 endpt1 AA 44 522 GG 457 0.0088 0.60 0.41 0.88 0.0198 A 0.62 G 0.38 hCV601962 rs544543 ZNF568 endpt1 GA 71 545 GO 579 0.6100 1.09 0.78 1.52 0.0198 A 0.62 G 0.38 hCV601962 rs544543 ZNF568 endpt1 GG 18 191 32 168 0.0240 0.51 0.29 0.92 0.0198 A 0.62 G 0.38 hCV8369472 rs1447351 MTNR1B endpt1 GG 42 347 59 322 0.0610 0.68 0.46 1.02 0.0471 A 0.48 G O.52 hCV8369472 rs1447351 MTNR1B endpt1 GA 65 586 65 632 0.7100 1.07 0.76 1.50 0.0471 A 0.48 G 0.52 hCV8369472 rs1447351 MTNR1B endpt1 AA 29 330 43 252 0.0088 0.53 0.33 0.85 0.0471 A 0.48 G 0.52 hCV22303 rs4552916 endpt1 AA 86 788 95 755 0.3600 0.87 0.65 1.17 0.0391 A 0.78 G 0.22 hCV22303 rs4552916 endpt1 GA 37 408 65 383 0.0038 0.55 0.37 0.82 0.0391 A 0.78 G 0.22 hCV22303 rs4552916 endpt1 GG 13 70 7 68 0.2400 1.73 0.69 4.33 0.0391 A 0.78 G 0.22 hCV601946 rs524802 ZNF568 endpt1 AA 17 175 29 156 0.0410 0.54 0.29 0.97 0.0203 A 0.37 G 0.63 hCV601946 rs524802 ZNF568 endpt1 AG 74 554 70 578 0.5700 1.1 0.79 1.53 0.0203 A 0.37 G 0.63 hCV601946 rs524802 ZNF568 endpt1 GG 45 536 68 471 0.0077 0.6 0.41 0.87 0.0203 A 0.37 G 0.63 hCV922535 rs748065 endpt1 AA 74 611 76 587 0.7300 0.95 0.69 1.3 0.0842 A 0.70 G 0.30 hCV922535 rs748065 endpt1 GA 48 541 81 520 0.0032 0.58 0.41 0.84 0.0842 A 0.70 C 0.30 hCV922535 rs748065 endpt1 GG 14 114 10 98 0.7000 1.17 0.52 2.63 0.0842 A 0.70 G 0.30 hDV70797856 rs17006217 endpt1 CC 2 14 0 13 1.0000 1E+09 0 Inf 0.0397 C 0.11 T 0.89 hDV70797856 rs17006217 endpt1 CT 25 255 45 231 0.0084 0.52 0.32 0.84 0.0397 C 0.11 T 0.89 hDV70797856 rs17006217 endpt1 TT 109 997 122 962 0.3000 0.87 0.67 1.13 0.0397 C 0.11 T 0.89 hCV11856381 rs2197089 rmi AG + AA 84 1006 129 970 0.0018 0.65 0.49 0.85 0.0420 A 0.54 G 0.46 hCV11856381 rs2197089 rmi GG 27 279 19 253 0.4300 1.26 0.70 2.27 0.0420 A 0.54 G 0.46 hCV16140621 rs2156552 rmi AT + AA 30 416 53 371 0.0045 0.52 0.33 0.82 0.0810 A 0.17 T 0.83 hCV16140621 rs2156552 rmi TT 81 876 95 854 0.2500 0.84 0.63 1.13 0.0810 A 0.17 T 0.83 hCV1682755 rs9424977 NEGR1 rmi CT + CC 73 941 112 893 0.0021 0.63 0.47 0.85 0.0780 C 0.48 T 0.52 hCV1682755 rs9424977 NEGR1 rmi TT 38 347 36 331 0.9200 1.02 0.65 1.62 0.0780 C 0.48 T 0.52 hCV27480853 rs3766430 SSBP3 rmi TC + TT 81 1029 124 992 0.0022 0.65 0.49 0.85 0.0820 C 0.44 T 0.56 hCV27480853 rs3766430 SSBP3 rmi CC 30 262 24 233 0.7200 1.10 0.64 1.88 0.0820 C 0.44 T 0.56 hCV2948766 rs4684343 CNTN4 rmi GA + GG 85 1042 129 1010 0.0022 0.65 0.50 0.86 0.0660 A 0.43 G 0.57 hCV2948766 rs4684343 CNTN4 rmi AA 25 244 18 213 0.5200 1.22 0.67 2.24 0.0660 A 0.43 G 0.57 hCV30534667 rs4996259 MAGI2 rmi AG + AA 47 667 79 595 0.0012 0.55 0.38 0.79 0.0330 A 0.30 G 0.70 hCV30534667 rs4996259 MAGI2 rmi GG 64 624 69 630 0.7300 0.94 0.67 1.32 0.0330 A 0.30 G 0.70 hCV30764105 rs12521915 ITGA2 rmi GC + GG 57 800 94 727 0.0008 0.57 0.41 0.79 0.0240 C 0.63 G 0.37 hCV30764105 rs12521915 ITGA2 rmi CC 54 491 54 498 0.9700 1.01 0.69 1.47 0.0240 C 0.63 G 0.37 hCV11231076 rs4857855 rmi CT + TT 46 405 42 414 0.6200 1.11 0.73 1.69 0.0130 C 0.82 T 0.18 hCV11231076 rs4857855 rmi CC 65 885 106 809 0.0005 0.58 0.42 0.79 0.0130 C 0.82 T 0.18 hCV11466079 rs157580 TOMM40 rmi GA + AA 98 1081 119 1029 0.1000 0.80 0.61 1.04 0.0830 A 0.61 G 0.39 hCV11466079 rs157580 TOMM40 rmi GG 13 207 29 195 0.0120 0.43 0.23 0.83 0.0830 A 0.61 G 0.39 hCV11592758 rs6265 BDNF rmi CT + TT 48 434 44 407 0.9000 1.03 0.68 1.54 0.0360 C 0.82 T 0.18 hCV11592758 rs6265 BDNF rmi CC 61 880 101 830 0.0010 0.59 0.43 0.81 0.0360 C 0.82 T 0.18 hCV11703905 rs1169301 TCF1 rmi CT + TT 67 661 72 632 0.5000 0.89 0.64 1.25 0.0730 C 0.69 T 0.31 hCV11703905 rs1169301 TCF1 rmi CC 44 627 76 593 0.0026 0.57 0.39 0.82 0.0730 C 0.69 T 0.31 hCV2195496 rs4982795 rmi CT + TT 92 1020 112 989 0.1300 0.81 0.61 1.06 0.0950 C 0.44 T 0.56 hCV2195496 rs4982795 rmi CC 18 266 35 234 0.0099 0.47 0.27 0.84 0.0950 C 0.44 T 0.56 hCV28960526 rs6853079 TSPAN5 rmi AT + TT 51 495 49 494 0.8400 1.04 0.70 1.54 0.0220 A 0.77 T 0.23 hCV28960526 rs6853079 TSPAN5 rmi AA 60 796 99 732 0.0007 0.57 0.42 0.79 0.0220 A 0.77 T 0.23 hCV29480044 rs10516433 TSPAN5 rmi CT + TT 51 491 49 494 0.8100 1.05 0.71 1.55 0.0210 C 0.78 T 0.22 hCV29480044 rs10516433 TSPAN5 rmi CC 60 795 99 733 0.0008 0.58 0.42 0.79 0 0210 C 0.78 T 0.22 hCV30136303 rs6914527 rmi GC + CC 77 797 85 813 0.6000 0.92 0.68 1.25 0 0130 C 0.40 G 0.60 hCV30136303 rs6914527 rmi GG 34 493 63 412 0.0005 0.48 0.31 0.72 0.0130 C 0.40 G 0.60 hCV30454150 rs10516434 TSPAN5 rmi CT + TT 51 489 49 491 0 8200 1.05 0.71 1.55 0.0200 C 0.78 T 0.22 hCV30454150 rs10516434 TSPAN5 rmi CC 60 799 99 734 0.0007 0.57 0.42 0.79 0.0200 C 0.78 T 0.22 hCV487868 rs6439132 rmi TC + CC 60 573 S3 563 0.7200 0.94 0.66 1.34 0.0490 C 0.26 T 0.74 hCV487868 rs6439132 rmi TT 51 718 85 662 0.0015 0.57 0.40 0.81 0.0490 C 0.26 T 0.74 hCV904974 rs439401 rmi TC + CC 101 1090 122 1025 0.0790 0.79 0.61 1.03 0.0980 C 0.61 T 0.39 hCV904974 rs439401 rmi TT 10 194 26 199 0.0160 0.41 0.20 0.85 0.0980 C 0.61 T 0.39 hCV15954645 rs2954029 rmi AA 36 376 31 344 0.8600 1.04 0.65 1.69 0.0421 A 0.53 T 0.47 hCV15954645 rs2954029 rmi AT 46 613 89 601 0.0004 0.53 0.37 0.75 0.0421 A 0.53 T 0.47 hCV15954645 rs2954029 rmi TT 28 296 28 278 0.8200 0.94 0.56 1.59 0.0421 A 0.53 T 0.47 hCV29684678 rs10486788 rmi CC 9 89 6 105 0.3000 1.72 0.61 4.83 0.0984 C 0.28 G 0.72 hCV29684678 rs10486788 rmi CG 40 526 67 481 0.0045 0.57 0.38 0.84 0.0984 C 0.28 G 0.72 hCV29684678 rs10486788 rmi GG 62 672 74 637 0.2000 0.80 0.57 1.12 0.0984 C 0.28 G 0.72 hCV621313 rs471364 C9orf52 rmi CC 2 16 1 24 0.4300 2.64 0.24 29.12 0.0972 C 0.13 T 0.87 hCV62l313 rs471364 C9orf52 rmi CT 20 288 41 263 0.0048 0.46 0.27 0.79 0.0972 C 0.13 T 0.87 hCV621313 rs471364 C9orf52 rmi TT 89 984 106 936 0.1500 0.81 0.61 1.08 0.0972 C 0.13 T 0.87 hDV70938014 rs17321515 rmi AA 34 363 31 328 0.9200 0.98 0.60 1.59 0.0770 A 0.52 C 0.48 hDV70938014 rs17321515 rmi AG 47 620 68 612 0.0009 0.55 0.38 0.78 0.0770 A 0.52 G 0.48 hDV70938014 rs17321515 rmi GG 30 309 29 287 0.8800 0.96 0.58 1.60 0.0770 A 0.52 G 0.48 hCV11446935 rs2409722 XKR6 rmi GG 39 325 39 337 0.8400 1.05 0.67 1.63 0.0560 G 0.51 T 0.49 hCV11446935 rs2409722 XKR6 rmi GT + TT 72 960 109 888 0.0019 0.62 0.46 0.84 0.0560 G 0.51 T 0.49 hCV10048483 rs2145270 rmi CC 22 187 16 166 0.5000 1.25 0.66 2.38 0.0730 C 0.38 T 0.62 hCV10048483 rs2145270 rmi CT + TT 89 1103 132 1059 0.0023 0.66 0.50 0.86 0.0730 C 0.38 T 0.62

TABLE 22 SNPs Associated with Risk of CHD in Placebo Arm of CARE TOTAL Allele 2 EVENTS PATIENTS (reference (placebo (placebo hCV rs gene symbol Allele 1 allele) arm) arm) hCV11513719 rs2967605 ELAVL1 T C 166 1367 hCV1323634 rs287475 T C 167 1372 hCV1323669 rs287354 G A 166 1373 hCV1729928 rs10509384 KCNMA1 A G 167 1368 hCV2221541 rs739161 T C 167 1373 hCV260164 rs6754295 T G 167 1373 hCV29011391 rs7557067 A G 167 1373 hCV29135108 rs6743779 KLF7 C A 167 1372 hCV3242952 rs2000571 A G 167 1372 hCV7537517 rs1501908 C G 166 1372 hCV7910239 rs1541296 FVT1 A G 166 1370 hCV11466848 rs1805419 BAX A G 167 1373 hCV2554721 rs7315519 RPH3A A G 167 1372 hCV2762168 rs3939286 T C 167 1371 hCV31237961 rs11950562 SLC22A4 A C 167 1371 hCV3168675 rs469930 G A 167 1371 hCV3170445 rs272893 SLC22A4 T C 167 1373 hCV610861 rs636887 T C 167 1373 hCV8785824 rs1412426 A C 167 1369 hCV8785827 rs992969 IL33 A G 167 1371 hDV70797856 rs17006217 C T 167 1373 hCV1026586 rs673548 APOB G A 167 1372 hCV11568668 rs1317538 KCNQ5 A G 166 1374 hCV1489995 rs4013819 LOC392281 G C 167 1372 hCV1948599 rs504527 CSMD2 C A 167 1370 hCV601962 rs544543 ZNF568 G A 167 1371 hCV601961 rs568654 ZNF568 A G 167 1373 hCV8369472 rs1447351 MTNR1B G A 167 1373 hCV461035 rs7746448 T C 167 1373 hCV30606396 rs10438978 T C 167 1372 hCV22303 rs4552916 G A 167 1373 hCV11856381 rs2197089 A G 148 1371 hCV15954645 rs2954029 A T 148 1371 hCV28960526 rs6853079 TSPAN5 A T 148 1374 hCV29480044 rs10516433 TSPAN5 C T 148 1375 hCV29684678 rs10486788 C G 147 1370 hCV30454150 rs10516434 TSPAN5 C T 148 1373 hCV30136303 rs6914527 G C 148 1373 hCV2195496 rs4982795 C T 147 1370 hCV2948766 rs4684343 CNTN4 G A 147 1370 hCV1253630 rs2071307 ELN A G 162 1371 hCV15746640 rs41271951 CTSS G A 165 1379 hCV16044337 rs2569491 KLK14 A G 164 1373 hCV16179493 rs2108622 CYP4F2 T C 165 1379 hCV1647371 rs3025000 VEGFA T C 161 1354 hCV1843175 rs3745535 KLK10 A C 165 1378 hCV2230606 rs13268 FBLN1 G A 164 1380 hCV2276802 rs381418 GBA C A 164 1380 hCV2536595 rs704 VTN A G 165 1383 hCV25472673 rs1805081 NPC1 C T 164 1380 hCV25596880 rs4647297 CASP2 C G 165 1380 hCV25603879 rs11542844 SCNN1A T C 165 1376 hCV25610819 rs8176740 T A 165 1374 hCV25614016 rs7607759 CAPN10 G A 165 1379 hCV25617571 rs2232580 LBP T C 165 1382 hCV25629396 rs3729823 MYH7 C G 164 1378 hCV25631989 rs1135983 ATF6 T C 158 1346 hCV25644901 ITGA9 G A 165 1379 hCV25926178 rs12882130 MARK3 G C 161 1352 hCV25926771 rs4906321 MARK3 C T 161 1350 hCV25927605 HLA-DPA1 T C 165 1375 hCV25941408 rs28497577 MYLK T G 163 1381 hCV2633049 rs2302006 CCL24 G T 164 1378 hCV2658421 rs3176975 APOH A C 164 1376 hCV2741051 rs2230806 ABCA1 T C 165 1382 hCV2741083 rs4149313 ABCA1 C T 165 1381 hCV2983035 rs9527026 KL A G 163 1377 hCV2983036 rs9527025 KL C G 165 1376 hCV3026189 rs11739136 KCNIP1 T C 165 1383 hCV435368 rs2812 PECAM1 T C 164 1380 hCV529706 rs428785 ADAMTS1 C G 164 1375 hCV529710 rs402007 ADAMTS1 C G 165 1382 hCV5478 rs1800574 TCF1 T C 165 1382 hCV7499212 rs1800127 LRP1 T C 165 1379 hCV7514870 rs1041981 LTA A C 165 1381 hCV7577801 rs11876 SLC9A3R2 T C 165 1374 hCV783184 rs510335 T G 164 1379 hCV7900503 rs3732379 CX3CR1 T C 165 1381 hCV8718197 rs1050998 CXCL16 G A 165 1383 hCV8784787 rs688976 A C 165 1381 hCV8901525 rs861539 KLC1 A G 161 1352 hCV8921288 rs1060621 GAPDH C A 158 1347 hCV9077561 rs1801274 FCGR2A G A 165 1381 hCV2741051 rs2230806 ABCA1 T C 165 1382 hCV435368 rs2812 PECAM1 T C 164 1380 hCV8921288 rs1060621 GAPDH C A 158 1347 hCV11689916 A T 158 1314 hCV12020339 rs4531 DBH T G 165 1374 hCV1243283 rs1716 ITGAE A G 165 1379 hCV1552894 rs434473 ALOX12 G A 165 1377 hCV1552900 rs1126667 ALOX12 A G 165 1379 hCV15851335 rs17610395 CPT1A T C 164 1379 hCV15954277 rs2236379 PRKCQ A G 165 1383 hCV16173091 rs2241883 FABP1 C T 165 1381 hCV1741111 rs1764391 C1orf212 T C 165 1380 hCV2143205 rs9666607 CD44 A G 165 1383 hCV22274761 rs11575194 IGFBP5 A G 165 1378 hCV2503034 rs1132356 BAIAP3 A C 164 1372 hCV2531086 rs10406069 CD22 A G 165 1379 hCV25473098 rs2241883 FABP1 G A 163 1371 hCV25610774 rs8176748 T C 165 1382 hCV25637309 rs3204849 CCRL2 A T 165 1378 hCV25651174 rs9277356 HLA-DPB1 G A 165 1375 hCV2769554 rs1805010 IL4R G A 165 1378 hCV370782 rs9841174 SERPINI2 C T 165 1376 hCV549926 rs1057141 Tap1or C T 165 1376 hCV7490135 rs1805082 NPC1 C T 165 1376 hCV8804621 rs1390938 SLC18A1 A G 164 1376 hCV8851065 rs9277343 HLA-DPA1 G C 165 1383 hCV9604851 rs1805002 CCKBR A G 165 1380 hCV997884 rs512770 A G 164 1370 hCV3135085 rs10795446 CUBN G T 164 1370 hCV3215409 rs267561 ITGA9 G A 165 1381 hCV7494810 rs1058587 GDF15 G C 165 1379 hCV783138 rs6046 F10 A G 163 1377 hCV795442 rs375947 IL12RB1 G A 164 1381 hCV818008 rs5918 ITGB3 C T 165 1381 Allele 1 Allele 2 hCV Freq. Freq. HR HR95L HR95U P value Model Endpoint hCV11513719 0.18 0.82 1.49 1.09 2.03 0.012 dom endpt1 hCV1323634 0.57 0.43 1.90 1.17 3.10 0.01 dom endpt1 hCV1323669 0.56 0.44 1.62 1.04 2.54 0.034 dom endpt1 hCV1729928 0.66 0.34 1.59 0.92 2.75 0.096 dom endpt1 hCV2221541 0.71 0.29 0.65 0.39 1.07 0.087 dom endpt1 hCV260164 0.76 0.24 2.37 0.88 6.39 0.088 dom endpt1 hCV29011391 0.76 0.24 2.34 0.87 6.30 0.094 dom endpt1 hCV29135108 0.32 0.68 1.42 1.04 1.94 0.027 dom endpt1 hCV3242952 0.22 0.78 1.31 0.96 1.78 0.084 dom endpt1 hCV7537517 0.64 0.36 2.37 1.25 4.48 0.0083 dom endpt1 hCV7910239 0.66 0.34 1.64 0.95 2.83 0.077 dom endpt1 hCV11466848 0.28 0.72 1.37 1.01 1.87 0.041 dom endpt1 hCV2554721 0.46 0.54 1.45 1.01 2.09 0.046 dom endpt1 hCV2762168 0.26 0.74 1.47 1.09 2.00 0.013 dom endpt1 hCV31237961 0.54 0.46 1.62 1.05 2.49 0.03 dom endpt1 hCV3168675 0.36 0.64 1.31 0.95 1.80 0.097 dom endpt1 hCV3170445 0.39 0.61 1.62 1.15 2.27 0.0056 dom endpt1 hCV610861 0.57 0.43 1.61 1.02 2.54 0.041 dom endpt1 hCV8785824 0.33 0.67 1.45 1.06 1.98 0.021 dom endpt1 hCV8785827 0.26 0.74 1.49 1.10 2.02 0.01 dom endpt1 hDV70797856 0.11 0.89 1.42 1.01 2.00 0.044 dom endpt1 hCV1026586 0.77 0.23 1.47 1.06 2.04 0.02 rec endpt1 hCV11568668 0.48 0.52 1.34 0.96 1.87 0.084 rec endpt1 hCV1489995 0.37 0.63 1.51 1.04 2.20 0.032 rec endpt1 hCV1948599 0.51 0.49 1.44 1.04 1.99 0.03 rec endpt1 hCV601962 0.38 0.62 1.44 0.98 2.11 0.066 rec endpt1 hCV601961 0.38 0.62 1.46 0.99 2.14 0.055 rec endpt1 hCV8369472 0.53 0.47 1.44 1.05 1.98 0.023 rec endpt1 hCV461035 0.60 0.40 1.30 0.96 1.77 0.094 rec endpt1 hCV30606396 0.17 0.83 1.35 0.98 1.87 0.064 het endpt1 hCV22303 0.22 0.78 1.32 0.96 1.81 0.087 het endpt1 hCV11856381 0.55 0.45 1.70 1.05 2.75 0.031 dom rmi hCV15954645 0.53 0.47 0.70 0.47 1.03 0.072 rec rmi hCV28960526 0.78 0.22 1.36 0.96 1.91 0.082 rec rmi hCV29480044 0.78 0.22 1.35 0.96 1.91 0.083 rec rmi hCV29684678 0.28 0.72 0.46 0.20 1.04 0.063 rec rmi hCV30454150 0.78 0.22 1.34 0.95 1.89 0.09 rec rmi hCV30136303 0.60 0.40 1.42 1.02 1.96 0.036 rec rmi hCV2195496 0.44 0.56 0.69 0.48 1.00 0.05 het rmi hCV2948766 0.58 0.42 1.62 0.97 2.69 0.064 het rmi hCV1253630 0.41 0.59 0.71 0.522 0.977 0.0354 dom endpt1 hCV15746640 0.08 0.92 0.55 0.322 0.932 0.0263 dom endpt1 hCV16044337 0.31 0.69 1.35 0.989 1.846 0.0587 dom endpt1 hCV16179493 0.31 0.69 0.76 0.559 1.032 0.0788 dom endpt1 hCV1647371 0.33 0.67 0.7 0.51 0.949 0.0218 dom endpt1 hCV1843175 0.36 0.64 1.4 1.016 1.921 0.0394 dom endpt1 hCV2230606 0.02 0.98 0.35 0.112 1.097 0.0717 dom endpt1 hCV2276802 0.37 0.63 0.72 0.518 0.994 0.0459 dom endpt1 hCV2536595 0.47 0.53 1.71 1.174 2.497 0.0052 dom endpt1 hCV25472673 0.39 0.61 1.47 1.048 2.062 0.0257 dom endpt1 hCV25596880 0.06 0.94 0.6 0.335 1.085 0.0914 dom endpt1 hCV25603879 0.03 0.97 0.43 0.176 1.046 0.0628 dom endpt1 hCV25610819 0.23 0.77 0.76 0.556 1.051 0.0988 dom endpt1 hCV25614016 0.16 0.84 0.63 0.436 0.92 0.0164 dom endpt1 hCV25617571 0.08 0.92 1.58 1.077 2.311 0.0191 dom endpt1 hCV25629396 0.01 0.99 0.16 0.023 1.163 0.0705 dom endpt1 hCV25631989 0.08 0.92 0.5 0.286 0.89 0.0182 dom endpt1 hCV25644901 0.05 0.95 1.93 1.272 2.939 0.002 dom endpt1 hCV25926178 0.38 0.62 1.45 1.041 2.029 0.0281 dom endpt1 hCV25926771 0.31 0.69 1.57 1.116 2.203 0.0094 dom endpt1 hCV25927605 0.03 0.97 0.3 0.094 0.927 0.0366 dom endpt1 hCV25941408 0.10 0.90 1.44 1.003 2.074 0.048 dom endpt1 hCV2633049 0.20 0.81 0.7 0.498 0.98 0.038 dom endpt1 hCV2658421 0.23 0.77 1.35 0.995 1.836 0.0539 dom endpt1 hCV2741051 0.28 0.72 0.65 0.471 0.884 0.0064 dom endpt1 hCV2741083 0.13 0.87 0.54 0.349 0.842 0.0064 dom endpt1 hCV2983035 0.15 0.85 1.34 0.968 1.865 0.0771 dom endpt1 hCV2983036 0.15 0.85 1.32 0.952 1.83 0.096 dom endpt1 hCV3026189 0.10 0.90 0.69 0.442 1.067 0.095 dom endpt1 hCV435368 0.47 0.53 1.61 1.106 2.353 0.013 dom endpt1 hCV529706 0.24 0.76 1.42 1.043 1.923 0.026 dom endpt1 hCV529710 0.24 0.76 1.42 1.05 1.933 0.023 dom endpt1 hCV5478 0.03 0.97 0.38 0.142 1.032 0.0578 dom endpt1 hCV7499212 0.02 0.98 1.87 1.081 3.232 0.0252 dom endpt1 hCV7514870 0.33 0.67 1.32 0.968 1.808 0.0791 dom endpt1 hCV7577801 0.22 0.78 0.66 0.475 0.93 0.017 dom endpt1 hCV783184 0.12 0.88 0.69 0.459 1.048 0.0821 dom endpt1 hCV7900503 0.28 0.72 0.72 0.524 0.975 0.034 dom endpt1 hCV8718197 0.44 0.56 0.71 0.519 0.969 0.0311 dom endpt1 hCV8784787 0.23 0.77 0.76 0.552 1.044 0.0897 dom endpt1 hCV8901525 0.37 0.63 0.73 0.534 0.991 0.0439 dom endpt1 hCV8921288 0.20 0.80 1.6 1.169 2.186 0.0033 dom endpt1 hCV9077561 0.50 0.50 1.47 1 2.164 0.0499 dom endpt1 hCV2741051 0.28 0.72 0.65 0.471 0.884 0.0064 dom endpt1 hCV435368 0.47 0.53 1.61 1.106 2.353 0.013 dom endpt1 hCV8921288 0.20 0.80 1.6 1.169 2.186 0.0033 dom endpt1 hCV11689916 0.48 0.52 1.33 0.963 1.849 0.0827 rec endpt1 hCV12020339 0.08 0.92 2.92 0.93 9.135 0.0663 rec endpt1 hCV1243283 0.33 0.67 1.57 1.012 2.444 0.0442 rec endpt1 hCV1552894 0.42 0.58 1.49 1.05 2.104 0.0254 rec endpt1 hCV1552900 0.42 0.58 1.48 1.047 2.098 0.0265 rec endpt1 hCV15851335 0.07 0.93 4.44 1.101 17.895 0.0362 rec endpt1 hCV15954277 0.26 0.74 0.24 0.076 0.75 0.0141 rec endpt1 hCV16173091 0.32 0.68 0.53 0.282 1.013 0.0546 rec endpt1 hCV1741111 0.30 0.70 0.46 0.203 1.034 0.0602 rec endpt1 hCV2143205 0.32 0.68 0.55 0.282 1.08 0.0828 rec endpt1 hCV22274761 0.04 0.96 16.7 2.327 119.75 0.0051 rec endpt1 hCV2503034 0.11 0.89 3.54 1.13 11.098 0.03 rec endpt1 hCV2531086 0.21 0.79 0.31 0.076 1.232 0.0955 rec endpt1 hCV25473098 0.31 0.69 0.59 0.319 1.084 0.0889 rec endpt1 hCV25610774 0.23 0.77 0.23 0.056 0.918 0.0375 rec endpt1 hCV25637309 0.39 0.61 0.47 0.278 0.805 0.0057 rec endpt1 hCV25651174 0.30 0.70 0.46 0.216 0.979 0.044 rec endpt1 hCV2769554 0.46 0.54 0.51 0.324 0.81 0.0042 rec endpt1 hCV370782 0.38 0.62 0.54 0.319 0.924 0.0243 rec endpt1 hCV549926 0.16 0.84 2.05 1.006 4.164 0.0481 rec endpt1 hCV7490135 0.47 0.53 1.38 0.981 1.929 0.0645 rec endpt1 hCV8804621 0.25 0.75 0.38 0.141 1.021 0.0551 rec endpt1 hCV8851065 0.28 0.72 0.51 0.24 1.093 0.0836 rec endpt1 hCV9604851 0.05 0.95 5.46 1.742 17.11 0.0036 rec endpt1 hCV997884 0.20 0.80 0.24 0.059 0.957 0.0432 rec endpt1 hCV3135085 0.33 0.67 0.74 0.533 1.034 0.0781 het endpt1 hCV3215409 0.42 0.58 1.48 0.955 2.28 0.0797 hom endpt1 hCV7494810 0.25 0.75 1.35 0.987 1.844 0.0608 het endpt1 hCV783138 0.11 0.89 0.66 0.417 1.045 0.0762 het endpt1 hCV795442 0.32 0.68 0.74 0.535 1.032 0.0765 het endpt1 hCV818008 0.15 0.85 1.33 0.956 1.839 0.0914 het endpt1 

What is claimed is:
 1. A method for reducing risk of hypertension in a human, the method comprising: a) receiving an identification of a human as having an increased risk for hypertension due to a polymorphism rs197922 in gene GOSR2 comprising A at position 101 of SEQ ID NO:1842 or T at its complement; and b) administering a therapeutic agent suitable for prevention or treatment of hypertension to said human.
 2. The method of claim 1, wherein said human is homozygous for said A or said T.
 3. The method of claim 1, wherein said human is heterozygous for said A or said T.
 4. A method for identifying a human as having an increased risk for hypertension, the method comprising: a) testing nucleic acid from said human for a polymorphism rs197922 in gene GOSR2 as represented by position 101 of SEQ ID NO:1842 or its complement by contacting said nucleic acid with an oligonucleotide comprising SEQ ID NO:4454 or a sequence fully complementary thereto that specifically hybridizes to A at said position 101 of SEQ ID NO:1842 or T at said complement; b) detecting said A or said T; and c) identifying said human as having an increased risk for hypertension due to the presence of said A or said T.
 5. The method of claim 4, wherein said method comprises nucleic acid amplification by polymerase chain reaction (PCR).
 6. The method of claim 4, wherein said human is homozygous for said A or said T.
 7. The method of claim 4, wherein said human is heterozygous for said A or said T.
 8. The method of claim 4, wherein said oligonucleotide is detectably labeled with a fluorescent dye.
 9. The method of claim 4, wherein said testing comprises allele-specific amplification, and further wherein said detecting comprises detecting the presence of an amplicon.
 10. A method for identifying a human as having an increased risk for hypertension, the method comprising: a) amplifying by polymerase chain reaction (PCR) a fragment of nucleic acid from said human that includes a polymorphism rs197922 in gene GOSR2 as represented by position 101 of SEQ ID NO:1842 or its complement to thereby create an amplicon containing said polymorphism; b) testing for said polymorphism by contacting said amplicon with an oligonucleotide comprising SEQ ID NO:4454 or a sequence fully complementary thereto that specifically hybridizes to A at said position 101 of SEQ ID NO:1842 or Tat said complement; c) detecting said A or said T; and d) identifying said human as having an increased risk for hypertension due to the presence of said A or said T.
 11. The method of claim 10, wherein said human is homozygous for said A or said T.
 12. The method of claim 10, wherein said human is heterozygous for said A or said T.
 13. The method of claim 10, wherein said oligonucleotide is detectably labeled with a fluorescent dye. 